Derivatives of 3,3-diphenylpropylamines

ABSTRACT

The invention concerns novel derivatives of 3,3-diphenylpropylamines, methods for their preparation, pharmaceutical compositions containing the novel compounds, and the use of the compounds for preparing drugs. More particularly, the invention relates to novel prodrugs of antimuscarinic agents with superior pharmacokinetic properties compared to existing drugs such as oxybutynin and tolterodine, methods for their preparation, pharmaceutical compositions containing them, a method of using said compounds and compositions for the treatment of urinary incontinence, gastrointestinal hyperactivity (irritable bowel syndrome) and other smooth muscle contractile conditions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of pending U.S. patent applicationSer. No. 12/105,016, filed Apr. 17, 2008; which is a continuation ofU.S. patent application. Ser. No. 11/201,756, filed Aug. 10, 2005, nowU.S. Pat. No. 7,384,980; which is a continuation of U.S. patentapplication Ser. No. 10/766,263, filed Jan. 27, 2004, now U.S. Pat. No.7,230,030; which is a continuation of U.S. patent application Ser. No.09/700,094, filed Jan. 2, 2001, now U.S. Pat. No. 6,713,464; which is a371 of International Patent Application No. PCT/EP99/03212, filed May11, 1999; which claims priority from European Patent Application No.98108608.5, filed May 12, 1998. Each of these applications is herebyincorporated herein in its entirety.

The present invention relates to novel derivatives of3,3-diphenylpropylamines, methods for their preparation, pharmaceuticalcompositions containing the novel compounds, and the use of thecompounds for preparing drugs.

In man, normal urinary bladder contractions are mediated mainly throughcholinergic muscarinic receptor stimulation. There is reason to believethat muscarinic receptors mediate not only normal bladder contractions,but also the main part of the contractions in the overactive bladderresulting in symptoms such as urinary frequency, urgency and urgeincontinence. For this reason, antimuscarinic drugs have been proposedfor the treatment of bladder overactivity.

Among the antimuscarinic drugs available on the market, oxybutynin iscurrently regarded as the gold standard for pharmacological treatment ofurge incontinence and other symptoms related to bladder overactivity.The effectiveness of oxybutynin has been demonstrated in severalclinical studies, but the clinical usefulness of oxybutynin is limiteddue to antimuscarinic side effects. Dryness of the mouth is the mostcommon experienced side effect which may be severe enough to result inpoor compliance or discontinuation of treatment (Andersson, K.-E., 1988,Current concepts in the treatment of disorders of micturition, Drugs 35,477-494; Kelleher et al. 1994).

Tolterodine is a new, potent and competitive, muscarinic receptorantagonist intended for the treatment of urinary urge incontinence anddetrusor hyperactivity. Preclinical pharmacological data show thattolterodine exhibits a favourable tissue selectivity in vivo for theurinary bladder over the effect on the salivation (Nilvebrant et al.,1997, Tolterodine—a new bladder-selective antimuscarinic agent, Eur. J.Pharmacol. 327 (1997), 195-207), whereas oxybutynin exhibits thereversed selectivity. Tolterodine is equipotent to oxybutynin at urinarybladder muscarinic receptors and the favourable tissue selectivity oftolterodine demonstrated in the preclinical studies has been confirmedin clinical studies. Thus a good clinical efficacy has been combinedwith a very low number of incidences of dry mouth and antimuscarinicside effects.

A major metabolite of tolterodine, the 5-hydroxymethyl derivative isalso a potent muscarinic receptor antagonist and the pharmacological invitro and in vivo profiles of this metabolite are almost identical tothose of tolterodine (Nilvebrant et al., 1997, Eur. J. Pharmacol. 327(1997), 195-207). Combined pharmacological and pharmacokinetic dataindicate that it is most likely that the metabolite gives a majorcontribution to the clinical effect in most patients.

WO 94/11337 proposes the active metabolite of tolterodine as a new drugfor urge incontinence. Administration of the active metabolite directlyto patients has the advantage compared to tolterodine that only oneactive principle (compound) has to be handled by the patient whichnormally should result in a lower variation in efficacy and side effectsbetween patients and lower risk of interaction with other drugs.

However, the introduction of an additional hydroxy group in thetolterodine results in an increased hydrophilic property of the newcompounds (3,3-diphenylpropylamines) compared to the parent compoundswhich normally results in a lower absorption/bioavailability, leading topre-systemic side effects or interactions due to non-absorbedantimuscarinic drug. In a method to circumvent this disadvantage,different prodrugs of the metabolite have been synthesized and testedfor their antimuscarinic activity, potential absorption throughbiological membranes and enzymatic cleavage.

It is an object of the present invention to provide novel derivatives of3,3-diphenylpropylamines. It is a further object of the presentinvention to provide new derivatives of 3,3-diphenylpropylamines whichwill be more useful as prodrugs for treatment of urinary incontinenceand other spasmogenic conditions that are caused by muscarinicmechanisms while avoiding the disadvantage of a too low absorptionthrough biological membranes of the drugs or an unfavourable metabolism.

A further object of the invention is to provide novel prodrugs ofantimuscarinic agents with superior pharmacokinetic properties comparedto present drugs as oxybutynin and tolterodine, methods for preparingthereof, pharmaceutical compositions containing them, a method of usingsaid compounds and compositions for the treatment of urinaryincontinence, gastrointestinal hyperactivity (irritable bowel syndrome)and other smooth muscle contractile conditions.

According to the present invention, novel 3,3-diphenylpropylamines areprovided, which are represented by the general formulae I and VII′

wherein R and R′ are independently selected froma) hydrogen, C₁-C₆ alkyl, C₃-C₁₀ cycloalkyl, substituted orunsubstituted benzyl, allyl or carbohydrate; orb) formyl, C₁-C₆ alkylcarbonyl, cycloalkylcarbonyl, substituted orunsubstituted arylcarbonyl, preferably benzoyl; orc) C₁-C₆ alkoxycarbonyl, substituted or unsubstituted aryloxycarbonyl,benzoylacyl, benzoylglycyl, a substituted or unsubstituted amino acidresidue; ord)

wherein R⁴ and R⁵ independently represent hydrogen, C₁-C₆ alkyl,substituted or unsubstituted aryl, preferably substituted orunsubstituted phenyl, benzyl or phenoxyalkyl wherein the alkyl residuehas 1 to 4 carbon atoms and wherein R⁴ and R⁵ may form a ring togetherwith the amine nitrogen; ore)

wherein R⁶ and R⁷ independently represent C₁-C₆ alkyl, substituted orunsubstituted aryl, preferably substituted or unsubstituted phenyl,benzyl or phenoxyalkyl wherein the alkyl residue has 1 to 6 carbonatoms; orf) an ester moiety of inorganic acids,g) —SiR_(a)R_(b)R_(c), wherein R_(a), R_(b), R_(c) are independentlyselected from C₁-C₄ alkyl or aryl, preferably phenyl,with the proviso that R′ is not hydrogen, methyl or benzyl if R ishydrogen, R is not ethyl if R′ is hydrogen,X represents a tertiary amino group of formula Ia

wherein R⁸ and R⁹ represent non-aromatic hydrocarbyl groups, which maybe the same or different and which together contain at least threecarbon atoms, and wherein R⁸ and R⁹ may form a ring together with theamine nitrogen,Y and Z independently represent a single bond between the (CH₂)_(n)group and the carbonyl group, O, S or NH,A represents hydrogen (¹H) or deuterium (²H),n is 0 to 12andtheir salts with physiologically acceptable acids, their free bases and,when the compounds can be in the form of optical isomers, the racemicmixture and the individual enantiomers.

The aforementioned compounds can form salts with physiologicallyacceptable organic and inorganic acids. Furthermore, the aforementionedcompounds comprise the free bases as well as the salts thereof. Examplesof such acid addition salts include the hydrochloride and hydrobromide.

When the novel compounds are in the form of optical isomers, theinvention comprises the racemic mixture as well as the individualisomers as such.

Preferably each of R⁸ and R⁹ independently signifies a saturatedhydrocarbyl group, especially saturated aliphatic hydrocarbyl groupssuch as C₁₋₈-alkyl, especially C₁₋₆-alkyl,

or adamantyl, R⁸ and R⁹ together comprising at least three, preferablyat least four carbon atoms.

According to another embodiment of the invention, at least one of R⁸ andR⁹ comprises a branched carbon chain.

Presently preferred tertiary amino groups X in formula I include thefollowing groups a) to h):

Group a) is particularly preferred.

The aforementioned tertiary amino groups X are described in WO 94/11337and the compounds according to the present invention can be obtained byusing the corresponding starting compounds.

In the compounds according to the present invention, the term “alkyl”preferably represents a straight-chain or branched-chain hydrocarbongroup having 1 to 6 carbon atoms. Such hydrocarbon groups may beselected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, pentyland hexyl. The term “cycloalkyl” denotes a cyclic hydrocarbon grouphaving 3 to 10 carbon atoms which may be substituted conveniently.

The term “substituted or unsubstituted benzyl” denotes a benzyl group—CH₂—C₆H₅ which is optionally substituted by one or more substituents onthe phenyl ring. Suitable substituents are selected from alkyl, alkoxy,halogen and nitro. Suitable halogen atoms are fluorine, chlorine andiodine atoms. Preferred substituted benzyl groups are 4-methylbenzyl,2-methylbenzyl, 4-methoxybenzyl, 2-methoxybenzyl, 4-nitrobenzyl,2-nitrobenzyl, 4-chlorobenzyl and 2-chlorobenzyl.

In the compounds according to the present invention the term “C₁-C₆alkylcarbonyl” denotes a group R—C(═O)— wherein R is an alkyl group asdefined hereinbefore. Preferred C₁-C₆ alkylcarbonyl groups are selectedfrom acetyl, propionyl, isobutyryl, butyryl, valeroyl and pivaloyl. Theterm “cycloalkylcarbonyl” denotes a group R—C(═O)— wherein R is a cyclichydrocarbon group as defined hereinbefore. The same counts to theselected carbonyl groups.

The term “aryl” denotes an aromatic hydrocarbon group such asphenyl-(C₆H₅—), naphthyl-(C₁₀H₇—) and anthryl-(C₁₄H₉—). Preferred arylgroups according to the present invention are phenyl and naphthyl withphenyl being particularly preferred.

The term “benzoyl” denotes an acyl group of the formula —CO—C₆H₅ whereinthe phenyl ring may have one or more substituents.

Preferred substituents of the aryl group and in particular of the phenylgroup are selected from alkyl, alkoxy, halogen and nitro. As substitutedbenzoyl groups 4-methylbenzoyl, 2-methylbenzoyl, 4-methoxybenzoyl,2-methoxybenzoyl, 4-chlorobenzoyl, 2-chlorobenzoyl, 4-nitrobenzoyl and2-nitrobenzoyl may be mentioned.

The term “C₁-C₆ alkoxycarbonyl” refers to a group ROC(═O)— wherein R isan alkyl group as defined hereinbefore. Preferred C₁-C₆ alkoxycarbonylgroups are selected from CH₃OC(═O)—, C₂H₅—OC(═O)—, C₃H₇OC(═O)— and(CH₃)₃COC(═O)—

and alicyclic alkyloxycarbonyl.

The term “amino acid residue” denotes the residue of a naturallyoccurring or synthetic amino acid. Particularly preferred amino acidresidues are selected from the group consisting of glycyl, valyl,leucyl, isoleucyl, phenylalanyl, prolyl, seryl, threonyl, methionyl,hydroxyprolyl.

The amino acid residue may be substituted by a suitable group and assubstituted amino acid residues, benzoylglycyl and N-acetylglycyl may bementioned.

The term “carbohydrate” denotes the residue of a polyhydroxy aldehyde orpolyhydroxy ketone of the formula C_(n)H_(2n)O_(n) or C_(n)(H₂O)_(n) andcorresponding carbohydrate groups are, for ex-ample, described inAspinal, The Polysaccharides, New York: Academic Press 1982, 1983. Apreferred carbohydrate group in the compounds according to the presentinvention is a glucuronosyl group, in particular a 1β-D-glucuronosylgroup.

The term “LG” as used herein denotes a leaving group selected fromhalogenides, carboxylates and imidazolides.

The term “Bn” as used herein denotes a benzyl group.

Suitable ester moieties of inorganic acids may be derived from inorganicacids such as sulfuric acid and phosphoric acid.

Preferred compounds according to the present invention are:

-   A) Phenolic monoesters represented by the general formulae II and    II′

-   -   wherein R¹ represents hydrogen, C₁-C₆ alkyl or phenyl.    -   Particularly preferred phenolic monoesters are listed below:

-   (±)-formic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-acetic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-propionic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (÷)-n-butyric acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-isobutyric acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   R-(+)-isobutyric acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2,2-dimethylpropionic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-acetamidoacetic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-cyclopentanecarboxylic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-cyclohexanecarboxylic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-benzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   R-(+)-benzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-4-methylbenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-methylbenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-acetoxybenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-1-naphthoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-naphthoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-4-chlorobenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-4-methoxybenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-methoxybenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-4-nitrobenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-2-nitrobenzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-malonic acid    bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl]ester,

-   (±)-succinic acid    bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl]ester,

-   (±)-pentanedioic acid    bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl]ester,

-   (±)-hexanedioic acid    bis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenyl]ester.

-   B) Identical diesters represented by the general formula III

-   -   wherein R¹ is as defined above.    -   Particularly preferred identical diesters are listed below:

-   (±)-formic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,

-   (±)-acetic acid    4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,

-   (±)-propionic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl    ester,

-   (±)-n-butyric acid    4-n-butyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl    ester,

-   (±)-isobutyric acid    2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl    ester,

-   (±)-2,2-dimethylpropionic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-(2,2-dimethyl-propionyloxy)-benzyl    ester,

-   (±)-benzoic acid    4-benzoyloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl    ester,

-   R-(+)-benzoic acid    4-benzoyloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl    ester,

-   (±)-pent-4-enoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)-phenyl    ester, cyclic oct-4-ene-1,8-dioate of Intermediate B, cyclic    octane-1,8-dioate of Intermediate B, poly-co-DL-lactides of    Intermediate B.

-   C) Mixed diesters represented by the general formula IV

-   -   wherein R¹ is as defined above    -   and    -   R² represents hydrogen, C₁-C₆ alkyl or phenyl with the proviso        that R¹ and R² are not identical.    -   Particularly preferred mixed diesters are listed below:

-   (±)-acetic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,

-   (±)-benzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,

-   (±)-benzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-acetoxymethylphenyl ester,

-   R-(+)-benzoic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-acetoxymethylphenyl ester,

-   (±)-isobutyric acid    4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,

-   R-(+)-isobutyric acid    4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,

-   (±)-2,2-dimethylpropionic acid    4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,

-   (±)-2,2-dimethylpropionic acid    4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,

-   (±)-benzoic acid    4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)=benzyl ester.

-   D) Benzylic monoesters represented by the general formula V

-   -   wherein R¹ is as defined above.    -   Particularly preferred benzylic monoesters are listed below:

-   (±)-formic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-acetic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-propionic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-butyric acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-isobutyric acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-2,2-dimethylpropionic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester,

-   (±)-benzoic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester.

-   E) Ethers and silyl ethers represented by the general formula VI

-   -   wherein at least one of R¹⁰ and R¹¹ is selected from C₁-C₆        alkyl, benzyl or —SiR_(a)R_(b)R_(c) as defined above and the        other one of R¹⁰ and R¹¹ may additionally represent hydrogen,        C₁-C₆ alkylcarbonyl or benzoyl.    -   Particularly preferred ethers and silyl ethers are listed below:

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-methoxymethylphenol,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenol,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-propoxymethylphenol,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-isopropoxymethylphenol,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-butoxymethylphenol,

-   (±)-acetic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-methoxymethylphenyl ester,

-   (±)-acetic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenyl ester,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxymethylphenol,

-   (±)-diisopropyl-[3-phenyl-3-(2-trimethylsilanyloxy-5-trimethylsilanyloxymethylphenyl)-propyl]-amine,

-   (±)-[3-(3-diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxyphenyl]-methanol,

-   (±)-diisopropyl-[3-(5-methoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine,

-   (±)-diisopropyl-[3-(5-ethoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropylamine,

-   (±)-[4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol,

-   (±)-acetic acid    4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-benzyl    ester,

-   (±)-4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenol,

-   (±)-acetic acid    4-(tert.-butyl-dimethylsilanyloxy)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl    ester,

-   (±)-{3-[(2-(tert.-butyl-dimethylsilanyloxy)-5-(tert.-butyldimethylsilanyloxymethyl)-phenyl]-3-phenylpropyl}-diisopropylamine,

-   (±)-[4-(tert.-butyl-diphenylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol,

-   (±)-acetic acid    4-(tert.-butyl-diphenylsilanyloxymethyl)-2-(3-diisopropylamino-1-phenylpropyl)-phenyl    ester,

-   (±)-4-(tert.-butyl-diphenylsilanyloxymethyl)-2-(3-diisopropylamino-1-phenylpropyl)-phenol,

-   (±)-{3-[2-(tert.-butyl-diphenylsilanyloxy)-5-(tert.-butyldiphenylsilanyloxymethyl)-phenyl]-2-phenylpropyl}-diisopropylamine,

-   (±)-acetic acid    4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,

-   (±)-benzoic acid    4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,

-   (±)-isobutyric acid    4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester,

-   (±)-2-(3-diisopropylamino-1-phenylpropyl)-4-(1β-D-glucuronosyloxymethyl)-phenol.

-   F) Carbonates and carbamates represented by the general formulae VII    and VIII

-   -   wherein Y, Z and n are as defined above and wherein R¹² and R¹³        represent a C₁-C₆ alkoxycarbonyl group or

-   -   wherein R⁴ and R⁵ are as defined above.    -   Particularly preferred carbonates and carbamates are listed        below:

-   (±)-N-ethylcarbamic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-N,N-dimethylcarbamic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-N,N-diethylcarbamic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-N-phenylcarbamic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester,

-   (±)-[2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenoxycarbonylamino]acetic    acid ethyl ester hydrochloride,

-   (±)-N-ethylcarbamic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-N-ethylcarbamoyloxybenzyl    ester,

-   (±)-N,N-dimethylcarbamic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-N,N-dimethylcarbamoyloxybenzyl    ester,

-   (±)-N,N-diethylcarbamic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-N,N-diethylcarbamoyloxybenzyl    ester,

-   (±)-N-phenylcarbamic acid    3-(3-diisopropylamino-1-phenylpropyl)-4-N-phenylcarbamoyloxybenzyl    ester,

-   (±)-{4-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenoxycarbonylamino]-butyl}-carbamic    acid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl    ester,

-   (±)-carbonic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester    ethyl ester,

-   (±)-carbonic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester    phenyl ester,

-   (±)-carbonic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxycarbonyloxymethylphenyl    ester ethyl ester,

-   (±)-carbonic acid    2-(3-diisopropylamino-1-phenylpropyl)-4-phenoxycarbonyloxymethylphenyl    ester phenyl ester.

-   G) 3,3-Diphenylpropylamines selected from    -   (i) compounds of the formulae IX and IX′

-   -   wherein o and p are the same or different and represent the        number of methylene units        CH₂        and may range from 0 to 6,    -   (ii) (±)-Benzoic acid        2-(3-diisopropylamino-1-phenylpropyl)-4-sulphooxymethyl-phenyl        ester    -   (iii) Poly-co-DL-lactides of        2-(3-diisopropylamino-phenylpropyl)-4-hydroxymethyl-phenol    -   (iv)        (±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-(1βD-glucuronosyloxymethyl)-phenol        having the formula

-   -   and    -   their salts with physiologically acceptable acids, their free        bases and, when the compounds can be in the form of optical        isomers, the racemic mixture and the individual enantiomers.

The present invention, moreover, relates to processes for thepreparation of the aforementioned compounds. In particular, according tothe present invention, the following processes are provided:

A process for the production of phenolic monoesters represented by thegeneral formula II

as defined above, which comprises treatment of a compound of the formula

with an equivalent of an acylating agent selected from

wherein LG represents a leaving group selected from halogenide,carboxylate and imidazolide and R¹ is as defined above, in an inertsolvent in the presence of a condensating agent.

Preferably, the acylating agent is selected from

wherein Hal represents a halogen atom, preferably a chlorine atom, andR¹ is as defined above.

A process for the production of phenolic monoesters represented by thegeneral formula II′

as defined above, which comprises treatment of two equivalents of acompound of the formula

with an acylating agent selected from

wherein Hal represents a halogen atom, preferably a chlorine atom.

Hence, in these processes, an Intermediate B having the formula

is treated with an equivalent of an acylating agent (e.g. an acylhalogenite or acyl anhydride) in an inert solvent and in the presence ofa condensating agent (e.g. amine) to provide phenolic monoesters offormula II or formula II′ (wherein n is 0-12), respectively, ifpolyfunctional acylating agents (e.g. acid halides, preferably acidchlorides of dicarboxylic acids) are used.

The Intermediate B as used in the processes for the production of the3,3-diphenylpropylamines according to the present invention can be inthe form of a racemic mixture or of optically active compounds inaccordance with the formulae shown below:

Alternatively, structures of formula II or II′ may be obtained byregioselective deprotection of a protected benzylic hydroxy group(chemically or enzymatically: T. W. Greene, P. G. M. Wuts, “ProtectiveGroups in Organic Chemistry”, 2nd Ed., J. Wily & Sons, New York 1991).

The identical diesters represented by the general formula III

as defined above can be prepared by a process which comprises treatmentof a compound of the formula

with at least two equivalents of the acylating agent R¹—C(═O)-LG asdefined above.

Thus, the aforementioned di-acyl compounds are readily accessible if anat least two-molar excess of an acylating agent is used in theabove-mentioned conversion of Intermediate B or, more general, ontreatment of compounds of formula I with acylating agents in thepresence of suitable catalysts. In the above process, the followingIntermediate A

wherein R′ denotes a benzyl group can be used instead of Intermediate B.The Intermediate A can be used in the form of a racemic mixture or ofoptically active compounds (similar to Intermediate B).

Benzylic monoestes represented by the general formula V

wherein R¹ is as defined above can be prepared by a process whichcomprises treatment of a compound of the formula

at room temperature and under anhydrous conditions with activated estersin the presence of enzymes selected from lipases or esterases.

Hence, this process relates to the preparation of phenols with paraacyloxymethyl substituents (cf. formula V). These compounds can beprepared in several chemical steps from intermediates such as formula I,where R represents hydrogen and R′ is hydrogen or any suitableprotective group which can be removed by known methods (T. W. Greene, P.G. M. Wuts, “Protective Groups in Organic Chemistry”, 2nd Ed., J. Wily &Sons, New York 1991) in the presence of the newly introduced substituentR¹CO. It was found, however, that the benzylic substituent R¹CO can beintroduced more conveniently and in only one step if Intermediate B istreated at room temperature and under anhydrous conditions withactivated esters (e.g. vinyl acylates, isopropenyl acylates) in thepresence of enzymes such as lipases or esterases.

The mixed diesters represented by the general formula IV

wherein R¹ and R² are as defined above can be prepared by a processwhich comprises acylation of the above-mentioned benzylic monoesterrepresented by the general formula V

wherein R¹ is as defined above or of a phenolic monoester represented bythe general formula II

as defined hereinbefore.

In general, mixed diesters of formula IV can be obtained by acylation ofcompounds of the general formula I wherein R and R′ are differentsubstituents selected from the group consisting of hydrogen, acylresidues or protecting groups that are cleavable under the acylationreaction conditions.

Ethers represented by the general formula VI

as defined hereinbefore wherein R¹¹ is hydrogen can be prepared by aprocess which comprises reacting a compound ofthe formula

with an alcohol R¹⁰—OH in the presence of an esterification catalyst.

A further process for the preparation of ethers represented by thegeneral formula VI

wherein R¹⁰ and R¹¹ are as defined hereinbefore, comprises acid or basetreatment of free benzylic alcohols selected from

wherein R¹⁰ is hydrogen and R¹¹ is as defined above or

wherein R¹² is hydrogen and R¹³ represents a C₁-C₆ alkoxycarbonyl groupor

wherein R⁴ and R⁵ are as defined aboveor of benzylic acylates selected from

wherein R¹ and R² are as defined hereinbefore in the presence ofsuitable hydroxy reagents.

Finally, ethers of formula VI can be prepared by a process whichcomprises treating a compound of the formula

wherein R¹⁰ is as defined above with an alkylating agent selected fromalkyl halogenides, alkyl sulphates and alkyl triflates, said alkyl grouphaving 1 to 6 carbon atoms.

In summary, regioselective modification of the benzylic hydroxy groupsis achieved either by acid or base treatment of benzylic acylates in thepresence of suitable hydroxy reagents (e.g. alcohols) or by catalyticether formation as described in the literature for other benzylicsubstrates (J. M. Saa, A. Llobera, A. Garcia-Raso, A. Costa, P. M. Deya;J. Org. Chem. 53: 4263-4273 [1988]). Both free benzylic alcohols such asIntermediates A and B or compounds of formulas II or VI (in which R¹⁰ ishydrogen) or formula VII (in which R¹² is hydrogen) as well as benzylicacylates such as formulae III, IV, V may serve as starting materials forthe preparation of benzylic ethers (B. Loubinoux, J. Miazimbakana, P.Gerardin; Tetrahedron Lett. 30: 1939-1942 [1989]).

Likewise the phenolic hydroxy groups are readily transformed into phenylethers (R¹¹=alkyl) using alkylating agents such as e.g. alkylhalogenides, alkyl sulphates, alkyl triflates or employing Mitsunobutype reaction conditions (Synthesis 1981, 1-28). Similarly, bothphenolic and alcoholic monosilyl ethers are obtained by regioselectivesilylation or by desilylation of bis-silyl ethers of Intermediate B asdescribed for other compounds in the literature (J. Paladino, C. Guyard,C. Thurieau, J.-L. Fauchere, Helv. Chim. Acta 76: 2465-2472 [1993]; Y.Kawazoe, M. Nomura, Y. Kondo, K. Kohda, Tetrahedron Lett. 26: 4307-4310[1987]).

Carbonates and carbamates represented by the general formulae VII andVIII

as defined hereinbefore can be prepared by a process which comprisesreacting a compound selected from the group consisting of

wherein R¹ is defined as above, n is 0 to 12, Bn is benzyl, one of R¹⁰or R¹¹ is hydrogen and the other one is as defined above with activatedcarbonyl compounds or carbonyl precursor reagents selected fromhaloformates, ketenes, activated esters, mixed anhydrides of organic orinorganic acids, isocyanates and isothiocyanates.

The coupling reactions can be carried out in inert solvents over periodsof several hours at temperatures from −10° C. to the refluxingtemperature of the solvent or reagent used to provide compounds of thegeneral formula VII where R¹² represents hydrogen, alkyl, aliphatic oraromatic acyl, or carbamoyl, and R¹³ represents —C(═O)—Y—R³, wherein Yand R³ represent O, S, NH and alkyl or aryl, respectively.Polyfunctional reagents give the corresponding derivatives. For example,diisocyanates or di-carbonylchlorides provide compounds of formula VIIIwhere X, Y have the meaning of O, S, or NH and n is zero to twelve. Theinvention, moreover, relates to pharmaceutical compositions comprisingone or more of the aforementioned 3,3-diphenylpropylamines. In otherwords, the compounds according to the present invention can be used aspharmaceutically active substances, especially as antimuscarinic agents.

They can be used for preparing pharmaceutical formulations containing atleast one of said compounds.

The compounds according to the present invention in the form of freebases or salts with physiologically acceptable acids, can be broughtinto suitable galenic forms, such as compositions for oral use, forinjection or for nasal spray administration, in accordance with acceptedpharmaceutical procedures. Such pharmaceutical compositions according tothe invention comprise an effective amount of the compounds of claims 1to 15 in association with compatible pharmaceutically acceptable carriermaterials, or diluents, as is well known in the art. The carriers may beany inert material, organic or inorganic, suitable for enteral,percutaneous or parenteral administration, such as water, gelatine, gumarabicum, lactose, microcrystalline cellulose starch, sodium starchglycolate, calcium hydrogen phosphate, magnesium stearate, talcum andcolloidal silicon dioxide. Such compositions may also contain otherpharmaceutically active agents, and conventional additives, such asstabilizers, wetting agents, emulsifiers, flavouring agents and buffers.

The composition according to the invention can e.g. be made up in solidor liquid form for oral administration, such as tablets, capsules,powders, syrups and elixirs in the form of sterile solutions,suspensions or emulsions for parenteral administration.

The compounds according to the invention may be used in a patchformulation. The compounds can be administered transdermally with areduced incidence of side effects and improved individual compliance.

The compounds and compositions can, as mentioned above, be used for thetreatment of urinary incontinence and other spasmogenic conditions thatare caused by muscarinic mechanisms. The dosage of the specific compoundwill vary depending on its potency, the mode of administration, the ageand weight of the patient and the severity of the condition to betreated. The daily dosage may, for example, range from about 0.01 mg toabout 5 mg, adminstered singly or multiply in doses e.g. from about 0.05mg to about 50 g each.

The invention will be further illustrated by the following non-limitingexamples and pharmacological tests.

I. EXPERIMENTAL 1. General

All compounds were fully characterized by ¹H and ¹³C NMR spectroscopy(Bruker DPX 200). The chemical shifts reported for ¹³C NMR spectra (50MHz, ppm values given) refer to the solvents CDCl₃ (77.10 ppm),dideuterio dichloromethane (CD₂Cl₂, 53.8 ppm), CD₃OD (49.00 ppm) orhexadeuterio dimethylsulphoxide (DMSO-d₆, 39.70 ppm), respectively. ¹HNMR data (200 MHz, ppm) refer to internal tetramethylsilane).

Thin-layer chromatography (tlc, R_(f) values reported) was conducted onprecoated 5×10 cm E. Merck silica gel plates (60F254), spots werevisualized by fluorescence quenching or spaying with alkaline potassiumpermanganate solution. Solvent systems: (1), ethyl acetate/n-hexane(30/70, v/v-%); (2), toluene/acetone/methanol/acetic acid (70/5/20/5,v/v-%); (3), n-hexane/acetone/diethylamine (70/20/10, v/v-%); (4),n-hexane/acetone/triethylamine (70/20/10, v/v-%); (5), ethylacetate/n-hexane/2-propanol/triethylamine (60/40/20/1, v/v-%); (6),ethyl acetate/triethylamine (90/10, v/v-%); (7),cyclohexane/acetone/acetic acid (80/20/0.5, v/v-%).

Optical rotations were measured at 589.3 nm and room temperature on aPerkin Elmer Polarimeter Type 241.

Melting points (mp) reported are uncorrected and were determined on aMettler FP 1 instrument.

IR spectra were taken from a Perkin-Elmer FTIR spectrometer Series 1610,resolution 4 cm⁻¹.

Gas chromatography-mass spectrometry (GC-MS): spectra (m/z values andrelative abundance (%) reported) were recorded on a Finnigan TSQ 700triple mass spectrometer in the positive (P-CI) or negative (N-CI)chemical ionization mode using methane or ammonia as reactant gas.Hydroxylic compounds were analyzed as their trimethylsilyl etherderivatives.

Combined liquid chromatography-mass spectrometry (LC-MS): WatersIntegrety System, Thermabeam Mass Detector (EI, 70 eV), m/z values andrelative abundance reported.

2. Synthesis of Intermediates A and B 3-Phenylacrylic acid 4-bromophenylester

An ice-cooled solution of 4-bromophenol (69.2 g) and cinnamoyl chloride(66.8 g) in dichloromethane (150 ml) was treated with triethylamine(40.6 g). After stirring for 18 hrs at room temperature the mixture waswashed with water (250 ml), 1 M aqueous HCl, and dried over anhydroussodium sulphate. Evaporation in vacuum left solid 3-phenylacrylic acid4-bromophenyl ester (121.0 g, 99.8% yield), m.p. 113.3° C., tlc: (1)0.83. NMR (CDCl₃): 116.85, 118.87, 123.49, 128.38, 129.06, 130.90,132.49, 134.02, 147.07, 149.84, 165.06.

(±)-6-Bromo-4-phenylchroman-2-one

A portion of the ester (60.0 g) was dissolved in a mixture of aceticacid (60 ml) and concentrated sulphuric acid (18 ml) and refluxed for 2hrs. After cooling, the reaction mixture was poured into ice water andthe product was isolated by extraction with ethylacetate. Evaporation ofthe solvent and recrystallization of the residue from boiling ethanol(150 ml) yielded 26.3 g (43.8% yield) of pure, crystalline(±)-6-bromo-4-phenylchroman-2-one, m.p. 117.8° C., tlc: (1) 0.67. NMR(CDCl₃): 36.56, 40.51, 117.29, 118.87, 127.47, 127.89, 128.33, 129.32,131.07, 131.79, 139.42, 150.76, 166.84.

(±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester

A suspension consisting of (±)-6-bromo-4-phenylchroman-2-one (85.0 g),anhydrous potassium carbonate (46.7 g), sodium iodide (20.5 g) andbenzyl chloride (40.6 g) in methanol (350 ml) and acetone (350 ml) wasrefluxed for 3 hrs. After evaporation of the solvents the residue wasextracted with diethyl ether (2×300 ml) and the extract was washed withwater (2×200 ml) and aqueous sodium carbonate. Drying (Na₂SO₄) androtoevaporation left 121.8 g (102.1% crude yield) of(±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid methyl ester asa light yellow oil, tlc: (1) 0.77; NMR (CDCl₃): 39.22, 40.53, 51.63,70.16, 113.10, 113.77, 126.46, 126.92, 127.88, 128.08, 128.34, 128.45,130.31, 130.55, 134.41, 136.44, 142.37, 154.94, 172.08.

(±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid

A solution of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acidmethyl ester (0.391 g, 0.92 mmol) in ethanol (5 ml) was treated at 50°C. with excess aqueous sodium hydroxide solution until the milkyemulsion became clear. The reaction mixture was then acidified (pH 3),evaporated and extracted with dichloromethane. The organic extract wasevaporated and the remaining oil was redissolved in a minimum of boilingethanol. The precipitation formed after 18 hrs at 4° C. was filtered offand dried in vacuo to yield 0.27 g (71.4%) of(±)-3-(2-Benzyloxy)-5-bromophenyl)-3-phenylpropionic acid, colourlesscrystals, m.p. 124.9° C.; tlc: (1) 0.15 (starting material methyl ester0.75); NMR (CDCl₃): 39.15, 40.26, 70.25, 113.21, 113.90, 126.62, 127.27,127.98, 128.17, 128.47, 128.54, 130.46, 130.68, 134.34, 136.45, 142.16,154.95, 177.65. LC-MS: 412/410 (14/11%, M^(+.)), 394/392 (15/13%),321/319 (17/22%), 304/302 (17/21%), 259 (24%), 194 (22%), 178 (21%), 167(65%), 152 (49%), 92 (100%). IR (KBr): 3434, 3030, 1708, 1485, 1452,1403, 1289, 1243, 1126, 1018, 804, 735, 698, 649. Calculated forC₂₂H₁₉BrO₃ (mol-wgt. 411.30): C, 64.25%; H, 4.66%; Br, 19.43%; O,11.67%. found:

C, 63.72%; H, 4.70%; Br, 19.75%; O 11.80%.

Alternatively, the crude reaction mixture from the above describedsynthesis of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acidmethyl ester was evaporated, redissolved in warm ethanol, and treatedwith excess aqueous potassium hydroxide solution. Acidification to pH 3(conc. hydrochloric acid) and cooling to 4° C. resulted in the formationof a solid, which was filtered off after 18 hrs, washed repeatedly withwater and dried to yield(±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid in 82% yield.

a) Resolution of 3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acidR-(−)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid

Warm solutions of (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid (815.6 g, 1.85 mol) and 1S,2R-(+)-ephedrine hemihydrate (232.1 g,1.85 mol) in 2000 ml and 700 ml, respectively, of absolute ethanol werecombined and then allowed to cool to 0° C. The precipitate formed wascollected, washed with cold ethanol and dried in vacuum to give 553.2 gof the ephedrinium salt of the title compound (m.p. 153° C., e.e. 65% asdetermined by NMR and HPLC). The salt was recrystallized twice fromboiling ethanol to giveR-(−)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid1S,2R-(+)-ephedrinium salt in 75% yield, colourless crystalls, m.p.158.6° C., e.e. 97.6% (HPLC). NMR (CDCl₃): 9.53, 30.90, 41.54, 42.83,61.45, 70.15, 70.42, 113.05, 113.68, 125.89, 126.03, 127.33, 127.85,128.19, 128.28, 128.45, 129.86, 130.70, 135.91, 136.65, 140.40, 144.09,155.20, 178.94.

1.2 g (2.0 mmol) of the ephedrinium salt were dissolved in a mixture ofacetone (5 ml) and ethanol (10 ml). After treatment with water (0.4 ml)and conc. (37%) aqueous hydrochloric acid (0.34 ml), the solution wasevaporated in vacuum, and the residue was redissolved in 1M aqueoushydrochloric acid (2 ml) and dichloromethane (10 ml). The organic phasewas separated, washed twice with water (2 ml), and evaporated to drynessto give R-(−)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid as acolourless oil which slowly solidified (0.4 g, 98% yield), m.p. 105.6°C. (from ethyl acetate/n-heptane); tlc: (7) 0.21; [α]_(D) ²⁰=−21.1(c=1.0, ethanol), e.e. 99.9% (HPLC). NMR: identical with the racemicacid.

S-(+)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid

The combined mother liquids from the above resolution andrecrystallizations were treated under stirring and cooling (18° C.) withexcess conc. aqueous hydrochloric acid. The precipitate (ephedriniumhydrochloride) was filtered off, and the filtrate was evaporated todryness. The residue was redissolved in dichloromethane (1.5 liter) andthen washed with several portions of 1 M aqueous hydrochloric acidfollowed by water. After drying (Na₂SO₄), filtration, and evaporation479 g of crude S-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid were obtained as a yellow viscous oil. The pure S-(+) enantiomericacid was converted into the 1R,2S(−)-ephedrine salt as described abovefor the R-(−) acid. Two recrystallizations from boiling ethanol providedcolourless crystals ofS-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid1R,2S-(−)-ephedrinium salt in 83% yield, m.p. 158.7° C., e.e. 97.8%(HPLC). NMR (CDCl₃): 9.47, 30.85, 41.54, 42.92, 61.48, 70.13, 70.30,113.04, 113.66, 125.89, 126.01, 127.32, 127.84, 128.18, 128.44, 129.83,130.68, 135.94, 136.63, 140.44, 144.13, 155.19, 178.94.

S-(+)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid was obtainedin quantitative yield from this ephedrinium salt by the method describedabove for the R-(−) acid, tlc: (7) 0.20, e.e. (NMR)>99%, mp 105.5° C.;[α]_(D) ²⁰=+22.6 (c=1.0, ethanol); NMR: identical with the racemic acid.

b) Enantioselective Synthesis of R-(−)- andS-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid

2-Benzyloxy-5-bromobenzaldehyde

To a solution of 0.1 mol of 5-bromo-2-benzaldehyde in THF (150 ml) wasadded 0.1 mol of K₂CO₃ and 0.11 mol of benzyl bromide. The mixture wasrefluxed for 2 hrs and water (500 ml) was added. After addition of ethylacetate (400 ml) and stirring the organic layer was washed with water,dried (sodium sulphate) and evaporated to dryness. The resultingslightly yellow solid of pure (tlc) 2-benzyloxy-5-bromobenzaldehyde wasused as such in the next step.

3-(2-Benzyloxy-5-bromophenyl)-acrylic acid

A mixture of 2-benzyloxy-5-bromobenzaldehyde (0.10 mol), malonic acid(15.0 g), and piperidine (2.0 ml) in 150 ml of pyridine was first heatedat 90° C. for 90 min and subsequently refluxed for 0.5 hrs. Aftercooling to room temperature, the reaction was poured on a mixture of ice(1 kg) and concentrated aqueous hydrochloric acid (250 ml). The solidmaterial that precipitated after stirring for 2 hrs. was collected bysuction and recrystallized from a minimum of boiling methanol.

3-[3-(2-Benzyloxy-5-bromophenyl)-acryloyl]-(4R)-4-phenyloxazolidin-2-one

Pivaloylchloride (7 g) was added dropwise at −30° C. to a stirredsolution of 3-(2-benzyloxy-5-bromophenyl)-acrylic acid (50.0 mmol) andtriethylamine (15.0 ml) in 200 ml of tetrahydrofuran. After anadditional hour the temperature was lowered to −50° C. and(R)-2-phenyloxazolidin-2-one (9.0 g) and lithium chloride (2.5 g) wereadded in one portion. The cooling bath was then removed and stirring wascontinued over 18 hrs. The reaction was diluted with water and3-[3-(2-benzyloxy-5-bromophenyl)acryloyl]-(4R)-4-phenyloxazolidin-2-onewas isolated by extraction with ethyl acetate.

3-[3-(2-Benzyloxy-5-bromophenyl)-(3S)-3-phenylpropionyl]-(4R)-4-phenyloxazolidin-2-one

To a precooled (−30° C.) mixture of copper-(I) chloride (21.0 g) anddimethylsulfide (45 ml) in dry tetrahydrofuran (150 ml) was addeddropwise an ethereal solution of phenyl-magnesiumbromide (0.3 mol). Themixture was stirred 20 min at the same temperature and then cooled to−40° C. A solution of3-[3-(2-Benzyloxy-5-bromophenyl)-acryloyl]-(4R)-4-phenyloxazolidin-2-one(50.0 mmol) in dry tetrahydrofuran (150 ml) was added during 10 min. Thecooling bath was removed and stirring was continued for 18 hrs. Themixture was quenched with half-saturated aqueous ammonium chloridesolution and the product was isolated by extraction with ethyl acetate.

S-(+)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid

A solution of the above described3-[3-(2-benzyloxy-5-bromophenyl)-(3S)-3-phenylpropionyl]-(4R)-4-phenyloxazolidin-2-onein tetrahydrofuran (300 ml) and water (100 ml) was cooled to 0° C. andthen treated with 30% aqueous hydrogen peroxide (20 ml) followed bysolid lithium hydroxide (4.3 g). Water was added after 2 hrs and thechiral auxiliary was removed by extraction with ethyl acetate. Theaqueous phase was acidified with aqueous hydrochloric acid (10%) andcrude S-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid wasextracted with tert.butyl-methylether.

HPLC analysis (Chiralpak AD, mobile phase hexane/2-propanol/trifluoroacetic acid (92:8:0.1, vol/vol-%); flow 1.0 ml/min, detection 285 nm)indicated an enantiomeric ratio 93:7 (retention times 14.8 min and 11.5min, respectively). The e.e. of 86% of the S-(+) enantiomer can beimproved to >98.5% by recrystallization of the diastereomeric saltsusing “nitromix” (Angew. Chem. Int. Ed. Engl. 1998, Vol. 37, p. 2349) or(1R,2S)-(−)-ephedrine hemihydrate as described above. TheS-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid was isolatedafter acidification of aqueous solutions of the diastereomeric salts. Itforms colourless crystals which gave an optical rotation of [α]_(D)²²=+21.6

(c=0.5, MeOH).

R-(−)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionic acid

Conjugate organocuprate addition of phenylmagnesiumbromide to3-[3-(2-benzyloxy-5-bromophenyl)-acryloyl]-(4S)-4-phenoyloxazolidin-2-oneas described above for the S-(+)enantiomer gave crystallineR-(−)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid in an e.e. of99.6% after two recrystallizations, [α]_(D) ²²=−21.7 (c=0.5, MeOH).

c) Synthesis of the R- and S-Enantiomers of Intermediate B (i)Phenylpropanol Route

(±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol

A solution of the methyl(±)-propionate (121.0 g) in 350 ml of drytetrahydrofuran was slowly added under an atmosphere of nitrogen to asuspension of lithium aluminiumhydride (7.9 g) in tetrahydrofuran (350ml). After stirring at room temperature for 18 hrs, 20% aqueous HCl wasadded dropwise and the product was isolated by repeated extraction withdiethyl ether. The combined extracts were gradually washed withhydrochloric acid, sodium hydroxide solution, distilled water, and thendried (Na₂SO₄) to give a light yellow viscous oil (108.8 g, 96.3% yield)after evaporation which gradually crystallized, m.p. 73.8° C., tlc: (1)0.47, (±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol. NMR(CDCl₃): 37.52, 39.52, 60.84, 70.54, 113.54, 113.83, 126.29, 127.30,127.51, 129.99, 128.24, 128.38, 129.99, 130.88, 135.69, 136.40, 143.53,155.12.

The same product was obtained after reduction of(±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid with lithiumaluminium hydride in tetrahydrofuran (30 min, 25° C.), 31% yield.

(±)-Toluene-4-sulphonic acid3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester

A cooled (5° C.) solution of(±)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropan-1-ol (108.0 g) indichloromethane (300 ml) was treated with pyridine (79.4 ml) and thenp-toluenesulphonyl chloride (60.6 g) in dichloromethane (200 ml). After18 hrs. at room temperature the solvent was removed in vacuum and theresidue was extracted with diethyl ether. The extract was washed withhydrochloric acid, water, and dried over anhydrous sodium sulphate togive (±)-toluene-4-sulphonic acid3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester as a light yellow oilafter concentration under reduced pressure (140.3 g, 93.6% yield), tlc:(1) 0.66. NMR (CDCl₃): 21.67, 33.67, 39.69, 68.58, 70.28, 113.21,113.76, 126.47, 127.84, 128.10, 128.25, 128.41, 128.51, 129.81, 130.26,130.42, 132.91, 134.39, 136.41, 142.16, 155.07.

(±)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine

A solution of the (±)-toluenesulphonate ((±)-toluene-4-sulphonic acid3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl ester, 139.3 g) inacetonitrile (230 ml) and N,N-diisopropylamine (256 g) was refluxed for97 hrs. The reaction mixture was then evaporated to dryness and theresidue thus formed was partitioned between diethyl ether (500 ml) andaqueous sodium hydroxide (2 M, 240 ml). The organic phase was washedtwice with water (250 ml) and then extracted with 1 M sulphuric acid.The aqueous phase was adjusted to about pH 12-13 and reextracted withether (500 ml). The organic phase was washed with water, dried (Na₂SO₄)and evaporated to provide(±)-[3-(2-benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine as abrown and viscous syrup (94.5 g, 77.9% yield), tlc: (2) 0.49. NMR(CDCl₃): 20.65, 20.70, 36.70, 41.58, 43.78, 48.77, 70.24, 113.52,126.02, 127.96, 128.20, 128.36, 129.82, 130.69, 136.34, 136.76, 144.20,155.15.

(ii) Phenylpropionamide Route

S-(+)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropionyl chloride

Thionylchloride (4.5 g, 2.8 ml, 37.8 mmol) and some drops ofdimethylformamide were added to a solution ofS-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid (10.3 g, 25mmol) in ethyl acetate (60 ml). The mixture was refluxed until tlccontrol indicated complete consumption of the starting material (2 hrs).Evaporation in vacuum gave the acid chloride as a light yellow liquid inalmost quantitative yield (10.7 g).

Conversion of an aliquot to the methyl ester showed a single spot in tlc(R_(f) 0.54, solvent system (7)).

S-(+)-N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide

A solution of S-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionylchloride (9.6 g, 22.3 mmol) in ethyl acetate (40 ml) was added dropwiseto a stirred and cooled (3° C.) solution of diisopropylamine (6.4 g,49.0 mmol) in 60 ml of ethyl acetate. The reaction was stirred for 18hrs at room temperature and then washed with water, aqueous hydrochloricacid (1 M) and half saturated brine. The organic phase was dried (sodiumsulphate) and evaporated to dryness. The colourless oily residue (10.7g, 97% yield) ofS-(+)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamideshowed a single spot on tlc: (R_(f) 0.70 (4)). NMR (CDCl₃): 18.42,20.46, 20.63, 20.98, 39.51, 41.44, 45.76, 48.63, 70.00, 112.84, 113.64,126.10, 126.45, 127.34, 127.78, 128.20, 128.36. 129.93, 130.59, 135.18,136.52, 143.52, 155.17, 169.61.

(±)-N,N-Diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide

The amide was prepared from diisopropylamine and the racemic acidchloride as described above for the S-(+) enantiomer. The viscouscolourless oil was dissolved in ethanol and the solution stored at −30°C. From this solution colourless crystals were obtained, m.p. 101.8° C.

(±)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine

To a stirred solution of(±)-N,N-diisopropyl-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionamide(11.8 g) in 40 ml of dry tetrahydrofuran was added 1 M lithium aluminiumhydride/tetrahydrofuran (36 ml). The reaction was refluxed for 4 hrs andthen quenched with the dropwise addition of water. After removal of theprecipitate the solvent was evaporated and the oily residue dissolved indiluted sulphuric acid. The aqueous phase was washed several times withdiethyl ether, adjusted to pH 10-12 (aqueous NaOH), and extracted withdiethyl ether. The extract was dried (sodium sulphate), filtered andevaporated to dryness in vacuum to leave 8.1 g (76.7%) of the titlecompound as a viscous colourless oil, tlc: (4) 0.86. The NMR spectrumcorresponds to the product, obtained from the tosylate precursor (seeabove).

S-(+)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine

Repetition of the reaction sequence by usingS-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid as thestarting material gaveS-(+)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine asa viscous colourless oil, [α]_(D) ²²=+18.5 (c=10.0, ethanol), e.e. of arepresentative batch 99.4%

R-(−)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine

Repetition of the reaction sequence by usingR-(−)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionic acid as thestarting material gaveR-(−)-[3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropyl]-diisopropylamine asa viscous colourless oil, [α]_(D) ²²=−17.3 (c=10.0, ethanol), e.e. of arepresentative batch 98.3%.

The optical purities were determined by chiral HPLC using Chiralpak ODcolumns.

(±)-4-Benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acidhydrochloride

An ethereal Grignard solution, prepared from the above (±)amine (22.8g), ethyl bromide (17.4 g) and magnesium (6.1 g) under an atmosphere ofnitrogen was diluted with dry tetrahydrofuran (200 ml) and then cooledto −60° C. Powdered solid carbon dioxide (ca. 50 g) was then added insmall portions and the green reaction mixture was warmed to roomtemperature. After the addition of an aqueous solution of ammoniumchloride (200 ml, 10%) and adjustment of the aqueous phase to pH 0.95, awhite solid was recovered by filtration to provide(±)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acidhydrochloride (14.7 g, 64.3% yield), m.p. 140° C. (dec.), tlc: (2) 0.33.NMR (CD₃OD): 17.07, 18.77, 33.55, 43.27, 56.50, 71.50; 112.89, 124.10,127.94, 129.07, 129.25, 129.34, 129.59, 129.66, 130.18, 131.60, 132.78,137.60, 143.30, 161.11, 169.70.

(±)-[4-Benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanolIntermediate A n=1

The (±)-hydrochloride was converted into its methyl ester (MeOH, tracesulphuric acid, 6 h reflux) and the free oily base thus obtained (28 g;tlc (2): R_(f) 0.46) was dissolved in dry diethyl ether (230 ml). Thissolution was slowly (2 h) dropped under a nitrogen atmosphere to asuspension of lithium aluminium hydride (1.8 g) in ether (140 ml). Afterstirring for 18 hrs, the reaction was quenched by the addition of water(4.7 ml). The organic phase was dried over anhydrous sodium sulphate,filtered and evaporated to dryness to provide(±)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol(26 g, 98.9% yield), as an oil which gradually crystallized, m.p. 86.4°C., tlc: (2) 0.32. NMR (CDCl₃): 20.53, 20.61, 36.87, 41.65, 44.14,48.82, 65.12, 70.09, 111.80, 125.77, 125.97, 126.94, 127.55, 128.08,128.37, 128.44, 133.27, 134.05, 134.27, 137.21, 144.84.

(±)-[4-Benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-[C²H]methanolIntermediate d₂-A (n=2)

Repetition of the above described reduction of the methylester of(±)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)benzoic acid by theuse of lithium aluminium deuteride gave(±)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-[C²H]methanol,colourless amorphous solid in 77% yield; tlc: (2) 0.33. NMR (CDCl₃):20.46, 20.55, 36.77, 41.62, 44.09, 48.77, multiplett centred at 64.96,70.05, 111.76, 125.72, 127.34, 128.03, 128.32, 128.38, 133.15, 133.99,137.17, 144.80, 155.52.

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenolIntermediate B n=1

A solution of Intermediate A (9.1 g) in methanol (100 ml) washydrogenated over Raneynickel (4.5 g) under ambient conditions. After 5hrs thin layer chromatography indicated complete hydrogenolysis. Thecatalyst was filtered off and the solution evaporated to dryness toleave an oil (6.95 g, 96.5% yield) which gradually solidified,(±)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol, m.p.50° C., tlc: (2) 0.15. NMR (CDCl₃): 19.42, 19.83, 33.22, 39.62, 42.27,48.27, 65.19, 118.32, 126.23, 126.55, 127.47, 128.33, 132.50, 144.47,155.38. Hydrochloride: colourless crystalls, m.p. 187-190° C. (withdecomposition)

S-(−)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol

Hydrogenolysis ofS-(−)-(4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl)-methanol(prepared from S-(+)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid as described for the racemic series) gave the title compound in 85%yield, colourless solid; m.p.≧50° C., [α]_(D) ²²=−19.8 (c=1.0, ethanol);NMR (CDCl₃): 19.58, 19.96, 33.30, 39.52, 42.10, 48.00, 65.40, 118.58,126.31, 126.57, 127.16, 127.54, 128.57, 132.63, 132.83, 144.55, 155.52.

S-(+) hydrochloride: colourless, non-hygroscopic solid, m.p. 186.4° C.(dec.); [α]_(D) ²²=+6.6 (c=0.5, water). NMR (DMSO-d₆): 16.58, 18.17,31.62, 41.37, 45.90, 54.02, 63.07, 115.18, 126.05, 126.37, 128.03,128.45, 129.04, 133.12, 143.88, 153.77.

R-(+)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol

Hydrogenolysis ofR-(+)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-methanol(prepared from R-(−)-3-(2-benzyloxy-5-bromophenyl)-3-phenylpropionicacid as described for the racemic series) gave the title compound in 87%yield, colourless solid; m.p.≧50° C., [α]_(D) ²²=+21.3 (c=1.0, ethanol).

R-(−) hydrochloride: colourless, non-hygroscopic solid, m.p. 179.8° C.(dec.); [α]_(D) ²²=−7.2 (c=0.5, water); NMR (DMSO-d₆): 16.59, 18.19,31.64, 41.38, 45.92, 54.07, 63.08, 115.19, 126.07, 126.39, 128.04,128.46, 129.05, 133.13, 143.89, 153.79. S-(+)-mandelate: m.p. 139.7° C.,[α]_(D) ²¹=+38.3 (c=1.0, ethanol)

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy-[²H₂]methylphenolIntermediate d₂-B (n=2)

A stirred suspension of lithium aluminium deuteride (0.1 g, 2.38 mmol)in 5 ml of dry diethyl ether was treated during 30 min at roomtemperature under an atmosphere of dry nitrogen with a solution of(±)-4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzoic acidmethyl ester (1.0 g, 2.17 mmol) in dry diethyl ether (5 ml). After anadditional stirring at room temperature for 18 hrs the reaction wasquenched by the dropwise addition of 0.17 ml of ²H₂O. The resultantprecipitation was filtered off, washed with small portions of ether, andthe combined organic phases were evaporated to dryness in vacuum toleave(±)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-[²H₂]methanol

as slightly yellow, viscous oil which gradually crystallized, m.p. 84.1°C.; tlc: (2) 0.33 (starting material 0.46), 0.725 g, 77.2% yield. NMR(CDCl₃): 20.46, 20.55, 36.77, 41.62, 44.09, 48.77, multiplett centred at64.30, 70.05, 111.76, 125.72, 125.94, 126.92, 127.34, 127.71, 128.03,128.32, 128.38, 133.15, 133.99, 137.17, 144.80, 155.52.

A solution of the above(±)-[4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]-[²H₂]methanol(0.129 g, 0.29 mmol) in a suspension of methanol (5 ml) and wetRaney-Nickel (0.1-0.2 g) was stirred at room temperature under anatmosphere of deuterium gas (²H₂). After 1 hr tlc indicated completedisappearance of the starting material. The mixture was filtered,evaporated and the residue was redissolved in diethyl ether (5 ml). Thesolution was washed with water (2×5 ml), dried over sodium sulphate,filtered and evaporated to dryness to leave a pale yellow oil, 76.3 mg,in 74.6% yield, which gradually solidified to give a colourless solid ofa m.p. range of 46-49° C. Tlc: (4) 0.57 (starting material 0.77). NMR(CDCl₂): 19.57, 19, 94, 33.33, 39.56, 42.18, 48.07, 48.43, multiplettcentred at 64.61, 118.47, 126.29, 126.58, 127.55, 127.94, 128.38,132.53, 144.53, 155.37. GC-MS (P-CI, ammonia, TMS derivative): 488.43(100%), 489.56 (70%), 490.56 (31%), 491.57 (8%).

n=2, deuterium

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy-[²H₂]methylphenolIntermediate d₂-B (iii) Heck-Cuprate-Route to Intermediate B

N,N-Diisopropyl-acrylamide

A solution of acroyl chloride (42.2 g, 40.6 ml, 0.467 mol) in 125 ml ofdichloromethane was slowly added to a cooled (0-5° C.) solution ofN,N-diisopropylamine in dichloromethane (500 ml). After 2 hrs theprecipitated ammonium salt was filtered off and the filtrate was washedwith 1M hydrochloric acid (3×100 ml), dried (sodium sulphate), andevaporated to dryness. N,N-diisopropyl-acrylamide was obtained as aslight yellow liquid in 48% yield and ca. 99% purity. NMR (CDCl₃):20.54, 21.25, 45.66, 48.10, 125.62, 130.70, 166.17.

(E)-N,N-Diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)acrylamide((E)-3-(2-Diisopropylcarbamoyl-vinyl)-4-methoxybenzoic acid methylester)

The reaction was carried out under an atmosphere of dry and oxygen-freenitrogen gas. All solvents and reagents were dried before use.

A stirred suspension consisting of N,N-dimethylglycine (6.0 mmol),anhydrous sodium acetate (40 mmol), methyl 3-bromo-4-methoxybenzoate (20mmol, 4.90 g), N,N-diisopropylacrylamide (24 mmol, 3.72 g),bis-(benzonitrile)-palladium-II chloride (1.5 mol %), and 20 ml ofN-methyl-2-pyrrolidinone was heated at 130° C. until no startingmaterial could be detected by tlc (starting material methyl3-bromo-4-methoxybenzoate: R_(f) 0.73; N,N-diisopropylacrylamide: R_(f)0.46; solvent system (1)). After cooling to room temperature 50 ml of anaqueous 2N HCl solution was added. The reaction was diluted withdichloromethane (50 ml) and the precipitated grey palladium metal wasfiltered off. The organic phase was washed with five portions (50 mleach) of 2N aqueous hydrochloric acid, dried (MgSO₄) and evaporated todryness. The remaining off-white solid was recrystallized from ethylacetate/n-hexane to give 4.40 g(E)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-acrylamide in69% yield, m.p. 139-140° C., tlc: (1) R_(f) 0.40. NMR (CD₂Cl₂): 21.22,22.10, 46.39, 48.87, 52.59, 56.61, 111.42, 123.39, 123.78, 125.54,130.32, 132.53, 135.07.

MS (EI, DI, 105° C.): 319 (M^(+.), 22), 304 (6%), 276 (8%), 219 (100%),187 (18%), 160 (7%).

(±)-N,N-Diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-3-phenylpropionamide((±)-3-(2-Diisopropylcarbamoyl-1-phenylethyl)-4-methoxybenzoic acidmethyl ester)

The reaction was carried out under an atmosphere of dry and oxygen-freenitrogen gas. All solvents and reagents were dried before use.

A dark green solution of lithium diphenylcuprate was prepared byaddition of phenyllithium solution (12 ml, 24 mmol, cyclohexane/diethylether) to a cooled (0° C.) and stirred suspension of copper-I bromidedimethylsulphide adduct (2.71 g, 13 mmol) in diethyl ether (40 ml). Thissolution was cooled to −78° C. and then subsequently solutions wereadded of trimethylchlorosilane (1.5 ml, 12 mmol) in diethyl ether (5 ml)followed by the above cinnamide (3.19 g, 10.0 mmol,(E)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-acrylamide) in10 ml of tetrahydrofuran. The reaction was stirred for one hour at −78°C., warmed to room temperature and then quenched by the addition of 150ml of a saturated aqueous solution of ammonium chloride. After 90 minthe organic phase was washed with two portions (100 ml) of halfsaturated aqueous sodium chloride, dried (MgSO₄) and evaporated todryness. The yellow oily residue was dissolved in a minimum of ethylacetate and purified by column chromatography on silica gel (mobilephase (1)). Evaporation of the combined fractions of the title compoundgave(±)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-3-phenylpropionamide

as a viscous slightly yellow syrup (1.8 g, 44% yield).

NMR (CD₂Cl₂): 19.45, 19.56, 19.74, 38.86, 44.87, 47.92, 50.80, 54.76,109.41, 121.32, 125.53, 128.10, 128.43, 128.78, 132.03, 143.20, 159.95,165.95, 168.87. MS (EI, DI, 105° C.): 397 (M^(+.), 41%), 366 (5%), 322(2%), 269 (3%), 255 (14%), 237 (7%), 165 (5%), 128 (12%), 91 (43%), 58(100%).

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol

A solution of(±)-N,N-diisopropyl-3-(2-methoxy-5-methoxycarbonylphenyl)-3-phenylpropionamide(0.79 g, 2.0 mmol) in 20 ml of tetrahydrofuran was cooled to 5° C. andthen treated with 2.5 ml of 1M LiAlH₄/THF. After stirring at roomtemperature for 18 hrs. finely powdered aluminium chloride (0.3 g) wasadded and stirring was continued for additional 4 hrs. The reaction wasquenched at 5° C. by the dropwise addition of water followed by aqueoussodium hydroxide solution. The mixture was diluted with diethyl ether(150 ml) and the organic phase was washed with half saturated brine,dried (sodium sulphate), and evaporated to dryness to give the titlecompound as a solid off-white foam. Tlc (2) 0.16, m.p. 48-51° C. Aportion of the material was converted into the hydrochloride (etherealhydrochloric acid), m.p. 186-189° C. (dec.).

Hydrogenolytic Deoxygenation ofS-(−)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol

A mixture ofS-(−)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol (683mg, 2.0 mmol, [α]_(D) ²²=−19.8 (c=1.0, ethanol)), platinium-on-carboncatalyst (120 mg) and acetic acid (1.0 ml) was diluted with ethylacetate (50 ml) and then hydrogenated at room temperature under apressure of 4 bar hydrogen gas for 5 hrs. The catalyst was filtered offand the filtrate was evaporated to leave an oil. The residue wasredissolved in dichloromethane (25 ml) and the solution was washed withaqueous sodium hydrogencarbonate solution. The organic phase wasconcentrated to dryness and the oily residue taken up in ethanol (7 ml).Addition of D-(−)-tartaric acid (300 mg) and storage of the clearsolution at −25° C. gave colourless crystals (310 mg) ofS-(−)-2-(3-diisopropylamino-1-phenylpropyl)-4-methylphenol D-(−)hydrogentartrate

in 33% yield, tlc: (4): 0.66 (starting material 0.31), [α]_(D) ²²=−26.7(c=1.0, methanol). NMR (CD₃OD): 17.98, 18.37, 20.69, 33.68, 43.12,56.33, 74.17, 116.31, 127.51, 129.11, 129.50, 129.70, 129.89, 130.41,144.57, 153.67, 176.88.

A portion of the tartrate was treated with aqueous sodiumhydrogencarbonate solution and the free base was isolated inquantitative yield as a colourless oil by extraction with ethyl acetateand evaporation of the extract. [α]_(D) ²²=−26.3 (c=1.0, methanol).

Preferred intermediates in the processes for the preparation of the3,3-diphenylpropylamines according to the present invention are:

-   (±)-3-(2-Benzyloxy-5-bromophenyl)-3-phenylpropanoic acid and its    salts,-   R-(−)-(2-Benzyloxy-5-bromophenyl)-3-phenylpropanoic acid and its    salts,-   S-(+)-(2-Benzyloxy-5-bromophenyl)-3-phenylpropanoic acid and its    salts,-   (±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy-[C²H₂]methyl-phenol,-   S-(−)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy-[C²H₂]methyl-phenol,-   R-(+)-2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxy-[C²H₂]methyl-phenol    and their salts.

3. Examples a) Phenolic Monoesters

aa) General Procedure

Esters of Carboxylic Acids

A stirred solution of(±)-2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol(Intermediate B, 1.71 g, 5.01 mmol) and acid chloride (5.00 mmolcarboxylic acid monochloride for compounds of formula II, 2.50 mmol forcompounds of formula II′) in 60 ml of dichloromethane was cooled to 0°C. and then triethylamine (0.502 g, 4.96 mmol for compounds of formulaII, 1.05 g, 9.92 mmol for compounds of formula II′), dissolved in 10 mlof dichloromethane, was added dropwise during 5-10 min. Stirring wascontinued for 18 hrs at room temperature, and then the mixture waswashed successively with water (25 ml), aqueous sodium hydrogencarbonate (5%, 25 ml), and water (25 ml). The organic phase was thendried (sodium sulphate) and evaporated under reduced pressure and at lowtemperature. The oily residues thus formed were finally exposed to highvacuum (2-4 hrs.) to remove traces of residual solvents.

The esters of formula II or II′ were obtained as colourless to lightyellow solids or viscous syrups in purities between 90% and 99% (tlc,HPLC, NMR).

Esters of N-Acylamino Acids

Phenolic Monoesters

To a solution of the respective amino acid (2.0 mmol) in 0.7 ml to 5 mlof N,N-dimethylformamide and 0.5 ml of triethylamine was added at 5° C.in one portion methyl chloroformate (2.0 mmol, 288 mg). After stirringfor 2 hrs. at the same temperature the cooling bath was removed and asolution of Intermediate B (2.0 mmol, 682 mg) in 5 ml of dichloromethaneand triethylamine (0.5 ml) was added. The reaction was allowed to stirfor 2-8 hrs and then diluted with diethyl ether (70 ml). Solidprecipitates were filtered off and the mixture was washed with aqueoussodium hydrogen sulphate solution (5%) and water. After drying (sodiumsulphate), filtration and evaporation in vacuum the residue was purifiedby flash chromatography on silica gel (eluent: solvent system (4)).N-acylamino acid esters were obtained as viscous oils or waxy solids inyields between 24% and 73%.

bb) Salt Formation (Example Hydrochloride)

A cooled (0° C.) solution of 4.94 mmol amino base in 30 ml of drydiethyl ether was treated under an atmosphere of nitrogen with 4.70 mmol(monoamines of formula II) or 9.4 mmol (diamines of formula II′)ethereal (1 M) hydrochloric acid. The oily precipitation was washedrepeatedly with dry ether and then evaporated in high vacuum. Theresidual product solidificated in most cases as an amorphous foam. Thehighly hygroscopic solids show a wide melting range above 100° C. (withdecomposition).

The following compounds were prepared according to the method describedabove and their analytical data are listed below:

(±)-Acetic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.47 (4), NMR (CDCl₃): 20.36, 20.68, 20.97, 36.59, 42.35, 43.83,48.76, 64.58, 122.69, 125.61, 126.22, 126.71, 127.96, 128.34, 136.82,138.97, 143.73, 147.77, 169.24; GC-MS/P-CI (ammonia, trimethylsilylderivative): 456.8 (100%), 398.4 (4%)

(±)-Propionic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.52 (4); NMR (CDCl₃): 20.44, 20.64, 27.67, 36.67, 42.21, 43.87,48.78, 64.70, 122.71, 125.62, 126.52, 126.78, 127.97, 128.53, 136.86,138.82, 143.82, 147.86, 172.68; GC-MS/P-CI (ammonia, trimethylsilylderivative): 470.38 (100%), 398.4 (4%)

(±)-n-Butyric acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.43 (4); NMR (CDCl₃): 13.77, 18.40, 20.43, 20.51, 20.59, 36.15,36.82, 42.16, 43.90, 48.83, 49.20, 64.58, 122.66, 125.98, 126.17,126.74, 127.33, 127.94, 128.33, 136.79, 138.91, 143.82, 171.88;GC-MS/N-Cl (methane, trimethylsilyl derivative): 482.3 (20%), 412.3(100%), 340.1 (33%), 298.1 (89%), 234.7 (15%); GC-MS/P-Cl (methane,trimethylsilyl derivative): 484.5 (100%), 468.4 (62%), 394.3 (22%);GC-MS/P-CI (ammonia, trimethylsilyl derivative): 484.4 (100%), 398.4(3%)

(±)-Isobutyric acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.43 (4); NMR (CDCl₃): 18.99, 19.11, 20.54, 34.21, 36.88, 41.84,43.91, 48.78, 64.61, 122.54, 125.57, 126.14, 126.81, 127.94, 128.34,136.84, 138.84, 143.89, 147.85, 175.36

R-(+)-Isobutyric acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.38 (4), starting material: 0.26; colourless oil (yield95%); NMR (CDCl₃): 19.02, 19.14, 19.96, 20.61, 34.26, 36.92, 41.87,43.90, 48.80, 64.84, 122.63, 122.63, 125.64, 126.19, 126.92, 127.98,128.39, 136.96, 138.76, 143.93, 147.97, 175.39.

Hydrochloride: colourless hygroscopic solid; [α]_(D) ²=+5.5 (c=1.0,chloroform); NMR (CDCl₃): 17.03, 17.53, 18.30, 18.52, 18.95, 19.12,31.23, 34.10, 41.69, 45.40, 54.22, 54.47, 64.00, 122.32, 126.62, 126.81,127.40, 128.06, 128.70, 133.88, 140.64, 142.25, 147.81, 175.89.

(±)-2,2-Dimethylpropionic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.49 (1); NMR (CDCl₃): 20.46, 20.66, 26.53, 27.34, 37.12, 39.21,41.46, 43.98, 48.81, 64.65, 122.42, 125.58, 126.16, 126.92, 128.37,134.27, 136.92, 138.82, 143.97, 148.02, 176.97; GC-MS/P-CI (ammonia,trimethylsilyl derivative): 498.8 (100%), 482.5 (10%), 398.4 (4%)

(±)-2-Acetamidoacetic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

((±)-2-[Diisopropylamino)-1-phenylpropyl]-4-(hydroxymethyl)phenyl2-(acetylamino)acetate)

NMR (CD₃OD): 20.33, 20.61, 22.17, 30.54, 42.39, 48.62, 51.04, 64.88,117.99, 124.73, 125.51, 127.01, 127.75, 129.31, 131.63, 137.33, 146.67,147.43, 171.47, 173.82

(±)-Cyclopentanecarboxylic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.66 (4), starting material Intermediate B (0.50), colourlessoil, yield: 82%. NMR (CDCl₃): 20.42, 25.87, 30.25, 36.57, 41.89, 43.97,47.15, 49.02, 64.63, 122.56, 125.60, 126.16, 126.81, 127.60, 127.94,128.35, 128.77, 136.74, 138.88, 143.85, 147.92, 175.05.

(±)-Cyclohexanecarboxylic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.67 (4), starting material Intermediate B (0.50), colourlessoil, yield: 93%. NMR (CDCl₃): 20.27, 25.40, 25.74, 29.03, 29.16, 36.29,41.82, 43.31, 44.08, 49.36, 64.62, 122.56, 125.68, 126.22, 126.92,127.92, 128.38, 136.65, 139.00, 143.72, 147.86, 174.40.

(±)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.31 (4); colourless syrup (99% yield, purity>95%); graduallycrystallized upon refrigeration; NMR (CDCl₃): 20.41, 20.51, 36.65,42.42, 43.85, 48.79, 64.70, 122.79, 125.74, 126.17, 126.83, 128.13,128.28, 128.58, 129.48, 130.25, 133.62, 137.21, 139.10, 143.67, 148.00,154.99.

R-(+)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

tlc R_(f) 0.3.0 (4); colourless syrup

Hydrochloride: colourless amorphous solid; [α]_(D) ²⁰=+14.9=1.0,chloroform);

NMR (CDCl₃): 17.06, 17.53, 18.25, 18.61, 31.23, 42.19, 45.49, 54.26,54.53, 64.09, 122.55, 126.77, 127.13, 127.58, 128.10, 128.50, 128.72,128.78, 129.02, 130.17, 133.96, 134.27, 140.81, 142.13, 147.91, 165.40.

(±)-4-Methylbenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.30 (4), starting material Intermediate B: 0.24; yield:quantitative, viscous light yellow oil; NMR (CDCl₃): 20.32, 20.50,21.78, 36.13, 42.35, 43.98, 49.29, 64.66, 122.79, 125.81, 126.19,126.70, 127.04, 128.30, 129.32, 129.76, 130.29, 136.94, 139.20, 143.61,144.46, 148.04, 165.07.

LC-MS: 459 (M^(+.), 3.5%), 444 (17%), 223 (2.5%), 195 (2%), 119 (48%),114 (100%).

(±)-2-Methylbenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

viscous colourless oil, tlc: (4) 0.64 (starting material R_(f) 0.51),yield 84%. NMR (CDCl₃): 20.44, 20.53, 21.86, 22.01, 36.74, 42.36, 43.87,48.81, 64.76, 122.93, 123.11, 125.71, 126.12, 126.88, 128.10, 128.48,130.76, 131.26, 131.70, 132.03, 132.79, 137.28, 139.00, 141.73, 143.72,148.04, 165.25. LC-MS: 459 (M^(+.), 21%), 444 (100%), 326 (1%), 223(10%), 213 (6%), 195 (9%), 165 (14%), 115 (94%), 91 (99%).

(±)-2-Acetoxybenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

colourless syrup, tlc: (4) 0.47 (starting material R_(f) 0.51), yield82%. NMR (CDCl₃): 20.39, 20.57, 20.96, 36.92, 42.29, 43.88, 48.87,64.64, 122.39, 122.64, 124.05, 125.80, 126.11, 126.75, 128.09, 128.32,132.23, 134.66, 137.27, 139.32, 143.64, 147.63, 151.37, 162.72, 169.73.LC-MS: 503 (M^(+.), 7%), 488 (59%), 446 (6%), 326 (22%), 223 (9%), 213(9%), 195 (9%), 163 (14%), 121 (100%), 114 (88%).

(±)-1-Naphthoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

colourless viscous oil, tlc: (4) 0.57 (starting material R_(f) 0.51),yield 82%. NMR (CDCl₃): 20.46, 20.58, 36.82, 42.46, 43.89, 48.76, 64.81,122.98, 124.51, 125.64, 125.79, 125.98, 126.15, 126.44, 126.94, 128.12,128.36, 128.65, 131.37, 131.82, 133.98, 134.45, 137.44, 139.08, 143.73,148.13, 165.49. LC-MS: 495 (M^(+.), 8%), 480 (100%), 213 (7%), 165 (8%),155 (95%), 127 (100%), 114 (90%).

(±)-2-Naphthoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

colourless slightly yellow viscous oil, tlc: (4) 0.57 (starting materialR_(f) 0.51), yield 71%. NMR (CDCl₃): 20.47, 20.59, 36.71, 42.59, 43.85,48.81, 64.82, 122.89, 126.89, 127.89, 128.19, 128.41, 128.68, 129.50,132.03, 132.55, 135.87, 137.22, 139.08, 143.83, 148.20, 165.14. LC-MS:495 (M^(+.), 7%), 480 (98%), 223 (8%), 213 (6%), 195 (6%), 165 (8%), 155(96%), 127 (100%), 114 (81%).

(±)-4-Chlorobenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.54 (4), starting material Intermediate B: 0.44; yield:quantitative, viscous light yellow oil; NMR (CDCl₃): 20.34, 20.50,36.41, 42.51, 43.84, 48.93, 64.66, 122.72, 125.82, 126.88, 127.27,128.06, 128.56, 128.96, 131.60, 133.80, 136.95, 139.30, 140.16, 143.60,147.87, 164.10. LC-MS: 479 (M^(+.), 1.5%), 464 (10%), 223 (2%), 195(2%), 165 (1.5%), 139 (25%), 114 (100%).

(±)-4-Methoxybenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.47 (4), starting material Intermediate B: 0.42; yield: 89%,viscous light yellow oil; NMR (CDCl₃): 20.31, 20.47, 36.43, 42.39,43.90, 48.97, 55.53, 64.71, 121.79, 122.86, 125.72, 126.14, 126.79,128.11, 128.27, 131.27, 131.77, 132.36, 132.84, 137.15, 139.01, 143.74,148.08, 163.92, 164.71. LC-MS: 475 (M^(+.), 3.5%), 460 (20%), 223 (2%),195 (2%), 135 (48%), 114 (100%).

(±)-2-Methoxybenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.40 (4), starting material Intermediate B: 0.42; yield: 98%,viscous light yellow oil; NMR (CDCl₃): 20.29, 20.42, 36.50, 41.92,44.02, 49.09, 55.95, 64.72, 119.10, 120.20, 122.86, 125.64, 126.10,126.82, 128.06, 128.30, 132.38, 134.32, 137.11, 139.01, 143.87, 148.00,159.82, 164.40. LC-MS: 475 (M^(+.), 3.5%), 460 (18%), 223 (1%), 195(1%), 135 (49%), 114 (100%).

(±)-4-Nitrobenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.44 (4), starting material Intermediate B: 0.42; yield: 78%,viscous yellow oil which slowly solidified; m.p. 123.6° C.; NMR (CDCl₃):20.47, 20.62, 36.52, 42.66, 43.70, 48.75, 64.69, 122.61, 123.72, 125.91,126.33, 127.04, 128.02, 128.37, 131.32, 134.86, 136.83, 139.55, 143.56,147.75, 150.93, 163.04. LC-MS: 490 (M^(+.), 1.5%), 475 (15%), 327(0.8%), 223 (3%), 195 (3%), 150 (15%), 114 (100%).

(±)-2-Nitrobenzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

Tlc: R_(f) 0.32 (4), starting material Intermediate B: 0.42; yield: 92%,viscous yellow oil which slowly solidified; NMR (CDCl₃): 20.39, 20.50,36.74, 42.14, 43.89, 48.71, 48.92, 64.59, 122.15, 123.95, 124.18,125.89, 126.25, 127.23, 127.99, 128.39, 129.95, 132.95, 133.08, 136.72,139.62, 143.64, 147.63, 148.15, 163.90. LC-MS: 490 (M^(+.), 1%), 475(11%), 327 (2.5%), 223 (2.5%), 195 (3%), 165 (3%), 150 (7%), 114 (100%).

(±)-N-Acetylglycine2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenylester/(±)-2-Acetamidoacetic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

((±)-2-[(Diisopropylamino-1-phenylpropyl]-4-(hydroxymethyl)phenyl2-(acetylamino)acetate)

NMR (CD₃OD): 20.33, 20.61, 22.17, 30.54, 42.39, 48.62, 51.04, 64.88,117.99, 124.73, 125.51, 127.01, 127.75, 129.31, 131.63, 137.33, 146.67,147.43, 171.47, 173.82.

(±)-Malonic acidbis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl]ester,tlc: R_(f) 0.38 (4); NMR (CDCl₃): 20.52, 20.62, 20.69, 36.95, 41.84,42.82, 43.89, 48.23, 64.83, 123.37, 127.36, 127.97, 128.42, 128.38,129.06, 131.55, 137.50, 138.90, 148.23, 148.32, 160.54

(±)-Succinic acidbis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl]ester,tlc: R_(f) 0.40 (4); NMR (CDCl₃): 20.54, 20.63, 20.73, 30.69, 36.91,41.80, 43.92, 48.20, 64.81, 122.60, 127.41, 127.93, 128.39, 129.31,131.80, 136.73, 138.92, 143.82, 148.17, 168.01

(±)-Pentanedioic acidbis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl]ester,tlc: R_(f) 0.43; NMR (CDCl₃): 20.47, 20.60, 32.87, 36.93, 41.82, 43.90,48.22, 64.81, 64.83, 122.85, 127.39, 127.99, 128.35, 129.31, 131.84,136.98, 138.94, 143.80, 147.40, 169.05

(±)-Hexanedioic acidbis-[2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl]ester,tlc: R_(f) 0.43; NMR (CDCl₃): 20.64, 23.40, 34.37, 36.95, 41.84, 43.88,48.25, 64.87, 122.88, 127.34, 127.97, 128.39, 129.33, 131.80, 136.99,138.94, 143.82, 147.65, 168.72

b) Identical Diesters

(±)-Identical diesters (formula III) were prepared and worked up asdescribed above with the exception that 2.4 mmol of both triethylamineand acyl chloride (R¹—COCl) were used. The physical properties weresimilar to the bases and salts described above.

Diesters of N-acylaminoacids were prepared as described for phenolicmonoesters with the exception that an additional molar equivalent ofacylating agent (mixed acid anhydride) was used.

In particular, the following compounds were prepared and theiranalytical data are given below:

(±)-Formic acid2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,tlc: R_(f) 0.65 (4). This diester was prepared from mixed formic aceticanhydride and Intermediate B as described for other substratespreviously (F. Reber, A. Lardon, T. Reichstein, Helv. Chim. Acta 37:45-58 [1954])

(±)-Acetic acid 4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzylester, tlc: R_(f) 0.76 (4); GC-MS/P-CI (ammonia): 426.3 (100%), 368.3(22%); GC-MS/P-CI (methane, trimethylsilyl derivative): 426.4 (64%),410.3 (16%), 366.3 (100%); hydrochloride, NMR (DMSOd₆)-16.50, 16.76,18.05, 20.94, 21.04, 27.02, 31.39, 41.28, 45.26, 53.80, 65.21, 123.39,126.84, 127.61, 127.85, 128.70, 134.41, 135.49, 142.68, 148.20, 169.32,170.42

(±)-Propionic acid2-(3-diisopropylamino-1-phenylpropyl)-4-propionyloxymethylphenyl ester,tlc: R_(f) 0.82 (4); NMR (CDCl₃): 20.53, 20.73, 21.14, 27.66, 36.73,42.10, 43.68, 48.65, 65.75, 122.65, 126.10, 127.01, 127.70, 128.34,128.78, 133.73, 136.81, 143.76, 148.45, 172.45, 174.21; GC-MS/P-CI(ammonia): 454.8 (100%), 438.5 (9%), 382.4 (27%)

(±)-n-Butyric acid4-n-butyryloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,tlc: R_(f) 0.86 (4); NMR (CDCl₃): 13.70, 13.76, 18.44, 20.53, 20.69,21.13, 36.14, 36.76, 37.09, 42.08, 43.73, 48.71, 65.64, 122.81, 125.97,126.97, 127.92, 128.35, 128.77, 133.78, 136.99, 143.76, 148.41, 171.68,173.40; GC-MS/P-CI (ammonia): 482.8 (100%), 396.4 (67%)

(±)-Isobutyric acid2-(3-diisopropylamino-1-phenylpropyl)-4-isobutyryloxymethylphenyl ester,tlc: R_(f) 0.83 (4), NMR (CDCl₃): 18.97, 19.10, 20.64, 20.67, 34.01,34.23, 36.98, 41.72, 43.70, 48.65, 65.61, 122.50, 126.18, 126.73,127.92, 128.13, 128.36, 133.90, 137.01, 143.85, 148.41, 175.17, 176.81;GC-MS/N-CI (methane): 480.3 (15%); GC-MS/P-CI (methane): 482.5 (63%),466.4 (18%), 394.3 (100%)

(±)-2,2-Dimethylpropionic acid3-(3-diisopropylamino-1-phenylpropyl)-4-(2,2-dimethylpropionyloxy)-benzylester, Tlc: R_(f) 0.96 (4); NMR (CDCl₃): 20.44, 20.75, 27.09, 27.24,37.18, 38.68, 39.15, 41.25, 43.66, 48.20, 65.50, 122.36, 126.32, 127.22,127.48, 127.83, 128.29, 133.99, 136.98, 143.87, 148.37, 176.70, 178.10;GC-MS/P-CI (methane): 510.5 (76%), 494.5 (21%), 408.4 (100%)

(±)-Benzoic acid4-benzoyloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester,tlc: R_(f) 0.80 (4); NMR (CDCl₃): 20.62, 36.95, 41.72, 43.89, 48.23,66.76, 122.22, 125.33, 127.36, 127.62, 127.89, 127.89, 127.97, 128.38,129.49, 130.52, 130.64, 131.15, 131.22, 131.98, 136.38, 137.66, 143.82,148.95, 164.77, 166.60

(+)-Benzoic acid4-benzoyloxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester

Hydrochloride: colourless solid; tlc: (4) 0.70, [α]_(D) ²⁰=+24.2 (c=1.0,chloroform). NMR (DMSO-d₆): 16.52, 17.99, 18.06, 26.99, 31.32, 53.94,65.98, 123.58, 127.65, 127.98, 128.62, 128.90, 129.02, 129.45, 129.71,130.10, 133.64, 134.32, 134.55, 135.60, 142.52, 148.37, 164.53, 165.76.

c) Mixed Diesters

Mixed diesters (formula IV) were prepared by acylation of the respectivebenzylic or phenolic monoesters. Working up and physical propertiescorresponded to the bases and salts described above.

In particular, the following compounds were prepared and theiranalytical data are given below:

(±)-Acetic acid2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,tlc: R_(f) 0.76 (4); NMR (CDCl₃): 20.62, 20.91, 33.25, 42.20, 42.28,48.23, 70.70, 122.96, 127.36, 127.97, 128.38, 128.73, 132.02, 135.41,137.11, 143.81, 149.35, 161.34, 168.95

(±)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-formyloxymethylphenyl ester,tlc: R_(f) 0.74 (4); NMR (CDCl₃): 20.60, 36.93, 41.72, 43.89, 48.23,70.71, 122.50, 125.33, 127.30, 127.89, 127.97, 128.36, 129.57, 130.65,131.13, 132.05, 135.41, 136.66, 143.80, 149.15, 161.35, 164.78

(±)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-acetoxymethylphenyl ester

Viscous colourless oil, tlc: R_(f) 0.70 (4); NMR (CDCl₃): identical withR-(+) enantiomer, see below.

R-(+)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-acetoxymethylphenyl ester

tlc: R_(f) 0.70 (4)

Hydrochloride: colourless non-hygroscopic solid [α]_(D) ²⁰=+27.1 (c=1.0,chloroform). NMR (CDCl₃): 17.14, 18.53, 21.04, 31.51, 42.25, 46.27,54.74, 65.58, 123.18, 127.07, 127.55, 127.61, 127.99, 128.80, 130.22,134.14, 134.81, 135.27, 141.44, 148.54, 165.19, 170.81.

(±)-Isobutyric acid4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester, tlc:R_(f) 0.77 (4); NMR (CDCl₃): 18.99, 19.12, 20.65, 21.05, 34.24, 37.02,41.79, 43.79, 48.72, 65.98, 122.75, 126.76, 127.14, 127.94, 128.39,128.84, 133.55, 137.04, 143.84, 148.56, 170.84, 175.18

(±)-Isobutyric acid4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester

colourless oil

Hydrochloride: colourless hygroscopic solid; [α]_(D) ²⁰=+14.6 (c=1.0,chloroform); NMR (CDCl₃): 16.89, 17.04, 18.31, 18.54, 18.92, 19.06,20.95, 31.49, 34.07, 41.64, 46.17, 54.55, 65.49, 122.91, 126.93, 127.48,127.83, 128.74, 134.50, 134.88, 141.61, 148.44, 170.67, 175.63.

(±)-2,2-Dimethylpropionic acid4-acetoxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester, tlc: R_(f)0.80 (4); NMR (CDCl₃): 20.63, 20.93, 27.19, 33.25, 37.49, 42.21, 42.25,48.22, 67.37, 123.18, 127.36, 127.84, 128.39, 131.16, 137.34, 143.84,148.29, 168.93, 178.40

(±)-2,2-Dimethylpropionic acid4-acetoxymethyl-2-(3-diisopropylamino-1-phenylpropyl)-phenyl ester, tlc:R_(f) 0.81 (4); NMR (CDCl₃): 20.60, 20.79, 27.09, 36.93, 37.35, 41.85,42.29, 48.25, 65.91, 122.36, 127.37, 127.99, 128.39, 129.38, 132.69,136.00, 136.85, 143.80, 170.45, 176.60

d) Benzylic Monoesters

A mixture consisting of Intermediate B (80 mg, 0.23 mmol), vinyl ester(0.4 ml), tert.-butyl methylether (18 ml), and lipase enzyme (1.0 g) wasgently shaken at room temperature. Benzylic formate, acetate, andn-butyrate were prepared from the corresponding vinyl ester donors usingSAM I lipase (Amano Pharmaceutical Co.). Benzoylation was achieved withvinyl benzoate in the presence of Lipozym IM 20 (Novo Nordisk), whereaspivalates and isobutyrates were obtained from the corresponding vinylesters under catalysis of Novozym SP 435 (Novo Nordisk). Tlc analysisindicated after 2-24 hrs complete disappearence of the starting material(R_(f)=0.45 (3)). The mixture was filtered and then evaporated underhigh vacuum (<40° C.) to give the carboxylic acid (R¹—CO₂H) salts of therespective benzylic monoesters as colourless to light yellow oils.

In particular, the following compounds were prepared and theiranalytical data are given below:

(±)-Formic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzylester, tlc: R_(f) 0.25 (2); NMR (CDCl₃): 19.43, 33.24, 39.61, 42.25,48.21, 68.44, 118.09, 127.34, 127.66, 128.31, 128.39, 133.97, 144.47,156.63, 161.32

(±)-Acetic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzylester, tlc: R_(f) 0.26 (2); NMR (CDCl₃): 19.45, 20.96, 33.26, 39.63,42.27, 48.23, 63.59, 118.00, 127.36, 128.33, 128.48, 128.53, 129.13,131.59, 133.88, 144.49, 155.74, 170.44

(±)-Propionic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzylester, tlc: R_(f) 0.45 (2); NMR (CDCl₃): 19.02, 19.43, 27.58, 33.20,39.61, 42.25, 48.21, 64.08, 118.30, 125.30, 127.03, 127.39, 128.31,130.12, 134.22, 144.51, 155.64, 173.22

(±)-Butyric acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzylester, tlc: R_(f) 0.54 (2); NMR (CDCl₃): 13.58, 18.40, 19.45, 33.29,35.88, 39.65, 42.23, 48.25, 63.96, 118.32, 124.55, 126.20, 127.35,128.32, 129.91, 134.22, 144.50, 155.60, 169.05

(±)-Isobutyric acid3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester, tlc: R_(f)0.56 (4); NMR (CDCl₃): 19.09, 19.45, 33.28, 33.59, 39.65, 42.29, 48.25,64.63, 118.35, 125.35, 127.03, 127.38, 128.35, 128.49, 129.79, 134.22,144.52, 155.65, 175.48

(±)-2,2-Dimethylpropionic acid3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzyl ester, tlc: R_(f)0.61 (4); NMR (CDCl₃): 19.41, 27.15, 33.24, 37.46, 39.61, 42.25, 48.21,65.10, 118.30, 125.32, 127.00, 127.34, 128.31, 129.42, 134.18, 144.47,155.61, 178.39

(±)-Benzoic acid 3-(3-diisopropylamino-1-phenylpropyl)-4-hydroxybenzylester, tlc: R_(f) 0.77 (4); NMR (CDCl₃): 18.01, 19.40, 33.24, 39.60,42.40, 48.20, 66.93, 117.13, 127.18, 127.81, 128.33, 129.98, 130.17,132.96, 133.58, 142.33, 156.95, 166.60

e) Ethers and Silyl Ethers

A mixture of Intermediate B (3.4 g, 10 mmol), methanesulphonic acid (2ml, 31 mmol), and alcohol R¹⁰—OH (50-150 ml) was stirred at roomtemperature until no starting material was detectable (2-24 hrs). Afterevaporation to dryness

(<35° C.) the residue was redissolved in aqueous sodium hydrogencarbonate solution (100-200 ml, 5%, w/v) and the solution was extractedwith ethyl acetate (75 ml). The organic phase was separated, dried(Na₂SO₄), filtered and evaporated to give bases of formula VI (R¹¹═H) ascolourless to light yellow oils.

Mixed ester ether derivatives, e.g. of Intermediate A, were prepared bybenzylic acylation of phenolic ethers, such as Intermediate A, accordingto the procedure described for examples of the structure of formula IV.

Hydrochlorides:

Molar equivalents of bases of formula VI (R¹¹═H), dissolved intert.-butyl methylether, and ethereal hydrochloric acid were combined atroom temperature. Oily precipitates were separated and dried in vacuum,crystalline hydrochlorides were isolated and recrystallized fromacetonitrile or acetone to give colourless crystalline material.

In particular, the following compounds were prepared and theiranalytical data are given below:

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-methoxymethylphenol, tlc:R_(f) 0.61 (4); GC-MS/P-CI (methane, trimethylsilyl derivative): 428.4(100%), 412.3 (49%), 396.3 (52%);

hydrochloride: amorphous hygroscopic colourless solid; m.p. 161° C.; NMR(CD₃OD): 17.39/18.75 (broad signals), 33.79, 43.13, 56.47, 58.00, 75.59,116.19, 120.79, 127.62, 129.04, 129.14, 129.42, 129.55, 130.43, 144.32,155.85)

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenol,

tlc: R_(f) 0.72 (4); GC-MS/P-CI (ammonia, trimethylsilyl derivative):444.8 (100%), 398.4 (6%);

hydrochloride: colourless non-hygroscopic crystals, m.p. 158-161° C.,NMR (CD₃OD): 15.43, 17.12, 18.82, 33.80, 56.49, 66.49, 73.62, 116.19,127.63, 128.99, 129.13, 129.36, 129.55, 130.58, 130.75, 144.32, 155.77

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-propoxymethylphenol, NMR(CDCl₃): 18.62, 19.44, 23.10, 33.24, 39.61, 42.26, 48.22, 71.87, 73.94,117.78, 124.95, 127.35, 127.57, 128.32, 128.47, 133.66, 134.23, 144.48,155.25

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-isopropoxymethylphenol, NMR(CDCl₃): 19.44, 22.32, 33.27, 39.65, 42.29, 48.25, 69.28, 72.10, 117.90,127.38, 128.03, 128.41, 131.10, 133.76, 134.37, 144.51, 154.65.

Hydrochloride: colourless crystals, m.p. 140.4° C., tlc (4) 0.61. LC-MS:383 (6%, [M-HCl]^(+.)), 368 (11%), 324 (1%), 223 (6%), 195 (3%), 165(2%), 155 (5%), 114 (100%). NMR (DMSO-d₆): 16.57, 18.09, 18.19, 22.29,31.58, 41.25, 45.87, 53.97, 69.26, 69.92, 115.28, 126.34, 127.08,127.25, 127.96, 128.45, 129.07, 129.70, 132.31, 143.88, 154.22.

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-butoxymethylphenol, NMR(CDCl₃): 13.75, 19.44, 19.75, 32.24, 33.28, 39.60, 42.20, 48.20, 72.45,117.87, 125.50, 127.29, 128.39, 133.70, 134.30, 144.47, 155.36

(±)-Acetic acid2-(3-Diisopropylamino-1-phenylpropyl)-4-methoxymethylphenyl ester, NMR(CDCl₃): 19.99, 20.62, 20.90, 33.33, 42.30, 48.21, 58.41, 75.94, 122.92,127.37, 127.95, 128.35 131.85, 136.99, 138.81, 143.88, 147.88, 168.95

(±)-Acetic acid2-(3-Diisopropylamino-1-phenylpropyl)-4-ethoxymethylphenyl ester, NMR(CDCl₃): 15.49, 19.94, 20.95, 33.23, 42.25, 48.25, 65.70, 73.73, 122.63,127.46, 127.95, 128.36, 131.65, 136.79, 139.71, 143.80, 147.66, 168.99

(±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxymethylphenol,NMR (CDCl₃): 0.10, 19.40, 19.43, 33.25, 39.65, 42.25, 48.20, 64.93,117.90, 124.90, 126.60, 127.35, 128.35, 128.48, 133.80, 137.15, 144.49,155.28

(±)-Diisopropyl-[3-phenyl-3-(2-trimethylsilanyloxy-5-trimethylsilanyloxymethylphenyl)-propyl]amine,NMR (CDCl₃): 0.10, 0.29, 19.40, 19.53, 33.28, 41.19, 42.27, 48.25,66.40, 121.37, 127.36, 128.25, 128.50, 136.42, 144.10, 154.98

(±)-(3-(3-Diisopropylamino-1-phenylpropyl)-4-trimethylsilanyloxyphenyumethanol,NMR (CDCl₃): 0.29, 0.33, 19.40, 19.53, 33.27, 41.16, 42.27, 48.23,65.22, 118.04, 124.99, 126.52, 127.30, 128.25, 134.16, 136.80, 144.14,155.06

(±)-Diisopropyl-[3-(5-methoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropyl]amine,NMR (CDCl₃): 0.28, 0.32, 19.39, 19.43, 33.28, 41.22, 42.33, 48.19,58.40, 75.95, 117.68, 124.92, 126.60, 127.35, 128.25, 128.55, 134.00,136.47, 144.16, 155.09

(±)-Diisopropyl-[3-(5-ethoxymethyl-2-trimethylsilanyloxyphenyl)-3-phenylpropyl]amine,NMR (CDCl₃): 0.28, 0.31, 15.50, 19.42, 19.58, 33.29, 41.17, 42.25,48.20, 65.70, 72.48, 117.50, 124.75, 126.39, 127.39, 128.25, 128.50,134.99, 136.28, 144.19, 154.28

(±)-[4-(tert.-Butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-phenyl]methanol,R_(f) 0.65 (3)

(±)-Acetic acid4-(tert.-butyl-dimethylsilanyloxy)-3-(3-diisopropylamino-1-phenylpropyl)-benzylester, NMR (CDCl₃): −4.92, −5.00, 19.40, 19.49, 20.40, 20.83, 23.49,33.25, 41.22, 42.25, 48.25, 72.55, 81.55, 121.24, 124.88, 127.40,128.26, 128.44, 128.48, 133.37, 135.74, 144.11, 155.20

(±)-4-(tert.-Butyl-dimethylsilanyloxymethyl)-2-(3-diisopropylamino-1-phenylpropyl)-phenol,tlc: R_(f) 0.70 (3); GC-MS/N-CI (methane, trimethylsilyl derivative):526.5 (59%), 454.3 (100%), 412.2 (14%), 340.1 (42%); GC-MS/P-CI(methane, trimethylsilyl derivative): 528.6 (100%), 512.5 (85%), 470.43(10%), 396.3 (31%)

(±)-Acetic acid4-(tert.-butyl-dimethylsilanyloxy)-2-(3-diisopropylamino-1-phenylpropyl)-phenylester, NMR (CDCl₃): −4.77, −4.88, 19.15, 20.65, 20.93, 24.77, 33.25,42.20, 48.20, 67.90, 122.79, 125.15, 127.44, 127.90, 128.41, 136.99,140.55, 143.85, 147.86, 168.95

(±)-{3-[2-(tert.-Butyl-dimethylsilanyloxy)-5-(tert.-butyl-dimethylsilanyloxymethyl)-phenyl]-3-phenylpropyl}-diisopropylamine,tlc: R_(f) 0.94 (3); GC-MS/N-CI (methane): 568.6 (62%), 454.3 (100%),438.2 (10%), 340.2 (58%), 324.8 (16%), 234.7 (78%); GC-MS/P-CI(methane): 570.6 (70%), 554.5 (52%), 512.5 (18%), 438.4 (24%)

(±)-Acetic acid 4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzylester, tlc: R_(f) 0.56 (5); GC-MS/P-CI (ammonia): 474.4 (100%), 416.4(54%); NMR (CDCl₃): 20.44, 20.56, 21.07, 36.73, 41.53, 44.01, 48.79,66.43, 70.00, 111.61, 125.75, 127.34, 127.55, 127.76, 127.90, 128.03,128.27, 128.39, 133.98, 136.98, 144.63, 156.05, 170.94

(±)-Benzoic acid4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester, tlc:R_(f) 0.87 (4); NMR (CDCl₃): 20.54, 20.60, 36.80, 41.51, 43.95, 48.67,66.83, 70.04, 111.66, 125.76, 127.35, 127.45, 127.78, 128.06, 128.27,128.30, 128.42, 128.85, 129.66, 130.55, 132.86, 134.05, 137.03, 144.75,156.08, 166.46; GC-MS/P-CI (ammonia): 536.5 (100%), 416.4 (42%)

(±)-Isobutyric acid4-benzyloxy-3-(3-diisopropylamino-1-phenylpropyl)-benzyl ester, tlc:R_(f) 0.77 (4); NMR (CDCl₃): 19.01, 20.62, 20.65, 34.04, 36.85, 41.54,43.97, 48.71, 66.15, 70.06, 111.62, 125.79, 125.96, 126.97, 127.24,127.55, 127.81, 128.08, 128.34, 128.45, 134.05, 137.10, 144.79, 156.00,177.01; GC-MS/P-CI (ammonia): 502.4 (100%), 416.4 (49%)

f) Carbamates and Carbonates

Mono N-Substituted Carbamates

A solution of 4.0 mmol of Intermediate B, benzylic ether (formula VI,R¹¹═H) or monoester of formula II in dichloromethane (20 ml) was treatedat room temperature for 16 hrs with isocyanate (4.8 mmol) ordiisocyanate (2.2 mmol). After washing with 10 ml aqueous sodiumhydrogen carbonate (5%, w/v), drying (Na₂SO₄) and evaporation oilyresidues or colourless solids of the free bases were obtained.

N-Disubstituted Carbamates

N,N-dialkyl-carbamoylchloride (4.4 mmol) was dissolved indichloromethane and dropped into a cooled (0° C.) and stirred mixtureconsisting of Intermediate B (4.0 mmol), dichloromethane (30 ml) andtriethylamine (7.0 mmol, 0.71 mg, 1 ml). Stirring was continued for 6hrs. The mixture was then washed with 5 portions (10 ml) of aqueoussodium hydrogen carbonate, dried (sodium sulphate), filtered andevaporated to give the carbamates as colourless oils or solids.

Bis-carbamates were prepared in like manner using Intermediate B andexcess isocyanate (4.8 mmol) and toluene as solvent at 65° C. over 18hrs.

Carbonates were prepared and worked-up according to the methodsdescribed for the preparation of compounds of formulae II to IV. Alkylchloroformates were used as acylation reagents.

Hydrochlorides:

The oils or solids were redissolved in tetrahydrofuran (10 ml). Additionof ethereal hydrochloric acid and evaporation to dryness in high vacuumgave crystalline or amorphous carbamate hydrochlorides.

In particular, the following compounds were prepared and theiranalytical data are given below:

(±)-N-Ethylcarbamic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester, tlc:R_(f) 0.38 (4); GC-MS/P-CI (ammonia, trimethylsilyl derivative): 486.8(100%), 413.4 (5%), 398.4 (6%); hydrochloride: m.p. 64° C. (withdecomposition); NMR (DMSO-d₆): 15.16, 16.68, 18.05, 18.13, 25.33, 31.26,35.46, 53.94, 62.65, 67.22, 123.04, 125.70, 126.72, 127.86, 128.67,135.42, 136.02, 140.07, 142.98, 147.53, 154.52

(±)-N,N-Dimethylcarbamic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

NMR (CDCl₃): 20.34, 20.66, 30.51, 36.33, 36.77, 42.00, 48.28, 50.21,65.65, 119.83, 123.44, 125.19, 126.60, 127.38, 127.54, 129.31, 136.62,143.33, 150.99, 155.67.

(±)-N,N-Diethylcarbamic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester

NMR (CDCl₃): 20.54, 20.66, 30.49, 35.61, 42.42, 48.31, 50.20, 65.56,119.43, 123.40, 125.33, 126.66, 126.99, 127.05, 136.30, 143.27, 149.13,154.97

(±)-N-Phenylcarbamic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester; NMR(CDCl₃): 20.52, 20.61, 36.91, 39.44, 42.25, 48.22, 62.66, 118.36,119.46, 123.50, 125.32, 127.11, 127.99, 130.15, 132.63, 139.65, 141.33,145.16, 152.21, 156.00

(±)-[2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenoxycarbonylamino]aceticacid ethyl ester hydrochloride

Tlc: R_(f) 0.14 (4); m.p. colourless crystals (from acetone, 21% yield);NMR (CDCl₃): 16.76, 16.86, 18.45, 20.96, 31.37, 42.20, 46.13, 54.56,65.50, 123.10, 126.98, 127.66, 128.72, 130.14, 134.05, 134.72, 135.22,141.37, 148.47, 165.12, 170.71

(±)-N-Ethylcarbamic acid3-(3-diisopropylamino-1-phenylpropyl)-4-N-ethylcarbamoyloxybenzyl ester,tlc: R_(f) 0.36 (3); NMR (CDCl₃): 15.00, 19.23, 19.40, 33.26, 36.00,39.62, 42.35, 48.12, 65.95, 118.30, 125.45, 127.08, 128.33, 130.37,134.24, 144.44, 155.44, 157.74

(±)-N,N-Dimethylcarbamic acid3-(3-diisopropylamino-1-phenylpropyl)-4-N,N-dimethylcarbamoyloxybenzylester

NMR (CDCl₃): 20.59, 20.66, 30.59, 35.96, 36.40, 36.74, 35.98, 42.03,48.26, 50.09, 67.09, 119.04, 123.23, 123.49, 125.01, 126.67, 127.72,129.33, 133.65, 143.43, 150.99, 155.63.

(±)-N,N-Diethylcarbamic acid3-(3-diisopropylamino-1-phenylpropyl)-4-N,N-diethylcarbamoyloxybenzylester

NMR (CDCl₃): 13.31, 13.64, 13.89, 20.33, 20.71, 31.57, 37.97, 41.55,42.37, 48.46, 51.00, 67.23, 120.00, 123.39, 124.82, 126.31, 126.95,127.33, 150.36, 157.18, 158.97.

(±)-{4-[2-(3-Diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenoxycarbonylamino]-butyl}-carbamicacid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester(formula VII′, X═Y═NH, n=4) tlc: R_(f) 0.60 (6); dihydrochloride m.p.142.5-145.6° C.

(±)-Carbonic acid2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester ethylester, R_(f) 0.67 (4)

(±)-Carbonic acid2-(3-diisopropylamino-1-phenylpropyl)-4-ethoxycarbonyloxymethylphenylester ethyl ester, R_(f) 0.87 (4)

g) Intramolecular Cyclic Diesters Via Ring Closing Metathesis (RCM)

Example (±)-Pent-4-enoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)-phenylester (x=y=2)

A cooled (4° C.) mixture of pent-4-enoic acid, isobutyl chloroformate,and triethylamine (each 5.84 mmol) in 10 ml of dichloromethane wasstirred 5 hrs under an atmosphere of dry nitrogen gas. The cooling bathwas then removed and both triethylamine (1.46 mmol) and2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol (1.46 mmol)were added in one portion. After 18 hrs the mixture was diluted withdichloromethane (30 ml), washed several times with water and finallyaqueous 5% sodium hydrogen carbonate solution. After drying (sodiumsulphate), filtration and evaporation the oily residue was re-dissolvedin a small volume of a solvent mixture consisting of ethylacetate/heptane/triethylamine (65/30/5, vol.-%) and applied on a silicagel flash chromatography column. Elution of the column with the samesolvent mixture, collection of the appropriate fractions, andevaporation of the combined fractions gave (±)-pent-4-enoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)phenylester as a pale yellow syrupy oil (50% yield), tlc: (4) 0.75. NMR(CDCl₃): 18.95, 20.77, 27.75, 28.87, 33.58, 36.83, 42.13, 43.72, 48.71,65.85, 70.55, 115.47, 115.99, 122.45, 126.26, 127.08, 127.96, 128.11,128.83, 133.73, 136.38, 136.79, 137.04, 143.77, 148.46, 171.11, 172.78.

Intramolecular Cyclic Diesters of 1,ω-dioic Acids and Intermediate BExample

Intramolecular cyclic diester of octane-1,8-dioic acid and2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol Grubbscatalyst (benzylidene-bis-(tricyclohexylphosphine)dichlororuthenium, 16mg, 0.002 mmol, 2 mol-%) was added to a solution of (±)-pent-4-enoicacid2-(3-diisopropylamino-1-phenylpropyl)-4-(pent-4-enoyloxymethyl)-phenylester (483 mg, 0.96 mmol) in dichloromethane (150 ml) and the mixturewas refluxed for 96 hrs. under an atmosphere of nitrogen gas, afterwhich all of the starting material was consumed as indicated by tlc. Themixture was filtered through a short pad of basic alumina, and thesolvent was removed in vacuum. Flash chromatography (solvent system (4))afforded the intermediate intramolecular cyclic diester ofoct-4-ene-1,8-dioic acid and2-(3-diisopropylamino)-1-(phenylpropyl)-4-hydroxymethyl-phenol (324 mg)as a colourless syrup (tlc: (4) R_(f) 0.68) in 71% yield, mixture of twogeometrical isomers.

NMR (CDCl₃, major isomer): 19.24, 20.61, 23.11, 25.62, 30.55, 33.53,35.02, 42.41, 48.29, 50.20, 65.30, 114.46, 124.33, 125.58, 127.15,128.70, 129.29, 131.10, 132.46, 139.54, 146.76, 147.98, 173.76, 174.39.

A portion of this material (140 mg) was dissolved in ethyl acetate (10ml) and hydrogenated at room temperature in the presence of palladium-oncarbon catalyst to afford the intramolecular cyclic diester ofoctane-1,8-dioic acid and2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethyl-phenol inessentially quantitative yield, 139 mg, colourless oil, tlc: (4) 0.71.

NMR (CDCl₃): 19.36, 20.73, 24.84, 25.28, 28.90, 29.70, 30.57, 33.72,34.37, 42.39, 48.26, 50.20, 65.26, 114.45, 124.37, 127.11, 128.67,129.29, 131.18, 132.45, 139.52, 146.77, 147.69, 173.90, 174.15.

Poly-co-DL-Lactides of Intermediate B

All reagents were dried over P₂O₅ in vacuum (<1 mbar) and at roomtemperature. The reactions were carried out at room temperature in anatmosphere of dry, oxygen-free nitrogen.

Low Molecular Weight Copolymer

A 15% solution of n-butyllithium (0.36 ml) was injected through a rubberseptum into a stirred solution of2-(3-diisopropylamino-phenylpropyl)-4-hydroxymethyl-phenol (100 mg,Intermediate B) and DL-dilactide (1.5 g) in 1.5 ml of dry toluene. Thepolymerization was allowed to proceed for 4 days at room temperature.Distilled water (10 ml) was then added in order to terminate thepolymerization. The organic phase was separated and slowly dropped into200 ml of methanol. The precipitated colourless oil was treated withwater (100 ml) and then dried in high vacuum for 48 hrs.

The copolymer was obtained in 72.7% yield. NMR analysis (see below)indicated an average molecular weight range of M_(n) 2000-4000 and aweight content of Intermediate B of about 8.4% (NMR). Tlc analysisshowed the absence of monomeric Intermediate B. Gel permeationchromatography (GPC) analysis showed a Mw of 1108 and a Mn of 702.

High Molecular Weight Copolymer

The high molecular weight copolymer was prepared as described above withthe exception that 3.0 g of DL-dilactide was used. Precipitation bymethanol gave a fluffy white solid which was carefully washed with waterand then dried as described to give the copolymer in 81% yield. NMRanalysis (see below) indicated an average molecular weight range ofM_(n) 4000-8000 and a weight content of Intermediate B of about 2.0%.Tlc analysis showed the absence of monomeric Intermediate B. Gelpermeation chromatography (GPC) showed a Mw of 9347 and a Mn of 6981.Differential scanning calorimetry (DSC) provided a Tg of 42.5° C.

NMR Analysis

The ¹H NMR resonance signals of the poly-lactyl chain were clearlyseparated from the copolymeric part of Intermediate B (solvent CDCl₃):

CH₃ resonances of the poly-lactyl chain: 1.30-1.60 ppm CH resonances ofthe poly-lactyl chain: 5.10-5.30 ppm CH resonances of the connectinglactyl units with the two hydroxy groups of Intermediate B: 4.8-5.0 ppmand 5.5-5.7 ppm. Polymer bound Intermediate B: 1.06-1.11 (CH₃),2.20-2.30 (CH₂ CH ₂), 2.40-2.80 (NCH ₂), 3.30-3.50 (NCH), 4.45-4.55(CHCH₂), 4.70-4.80 (CH ₂—OCO-lactyl), 6.70-7.30 (aryl CH).

h) Inorganic Ester Example (±)-Benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-sulphooxymethyl-phenyl ester

Hydrochloride

To a stirred solution of chlorosulphonic acid (116 mg, 1.0 mmol) in 5 mlof dry diethyl ether was slowly added at 0° C. a solution of (±)-benzoicacid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl ester(445.6 mg, 1.0 mmol) in 3 ml of dry diethyl ether. The gel formedimmediately during the addition was stirred at room temperature until itbecame a crystalline consistency (ca. 1 hr). The precipitate was washedseveral times with diethyl ether and then dried in vacuum to give 0.52 g(46% yield) colourless crystals, m.p. 63-65° C. NMR (CDCl₃): 16.85,17.03, 18.32, 18.49, 32.01, 42.29, 46.23, 55.23, 55.50, 69.24, 122.52,126.94, 127.15, 129.04, 129.76, 130.25, 133.89, 134.93, 136.85, 141.87,147.80, 165.19.

i) Benzylic 1-O-β-D-glucuronide of2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenol((±)-2-(3-Diisopropylamino-1-phenylpropyl)-4-(1β-D-glucuronosyloxymethyl)-phenol)

A solution of methyl 2,3,4-triacetyl-1-α-D-glucuronosylbromide (2.07 g,4.64 mmol) in 24 ml of dry toluene was cooled to −25° C. under anatmosphere of nitrogen and then treated with a solution of (±)-benzoicacid 2-(3-diisopropylamino-1-phenylpropyl)-4-hydroxymethylphenyl esterin 7 ml of toluene. To this mixture was added dropwise with stirring andunder protection from light a solution of silver triflate in 14 ml oftoluene (immediate formation of a white precipitate). The cooling bathwas removed after 15 min and pyridine (0.38 ml) was added. The mixturewas diluted with ethyl acetate (200 ml), filtered and the clear yellowfiltrate was washed sequentially with aqueous solutions of sodiumthiosulphate (5%), sodium hydrogen carbonate (5%), and sodium chloride(20%). The solution was dried with solid sodium sulphate, treated withcharcoal, filtered and evaporated to dryness. The waxy residue wasre-dissolved in a small volume of a solvent mixture consisting of ethylacetate/heptane/triethylamine (65/30/5, vol.-%) and applied on a silicagel flash chromatography column. Elution of the column with the samesolvent mixture, collection of the appropriate fractions, andevaporation of the combined fractions gave

(±)-benzoic acid2-(3-diisopropylamino-1-phenylpropyl)-4-(2,3,4-triacetyl-1β-D-glucuronosyloxymethyl)-phenylester, colourless syrup, tlc (4) 0.70 (starting amine: 0.31, bromoglycoside: 0.23), yield 14%.

NMR (CDCl₃, mixture of diastereomers): 20.41, 20.50, 20.60, 20.65,20.84, 36.49, 42.44, 43.65, 48.73, 52.91, 69.46, 70.43, 71.12, 72.11,72.60, 73.99, 99.19, 122.91, 126.23, 126.38, 126.54, 127.60, 127.92,128.06, 128.09, 128.31, 128.59, 129.38, 130.22, 133.67, 134.31, 137.41,143.52, −148.46, 164.82, 167.26, 169.21, 169.39, 170.07.

A portion (350 mg) of the above described material was dissolved andhydrolyzed in a solvent mixture consisting oftetrahydrofuran/methanol/aqueous potassium hydroxide (excess, 12 hrs,22° C.). The mixture was evaporated, re-dissolved in 5 ml of water andthe pH was adjusted to 8.3. This solution was applied to achromatography column charged with prewashed XAD 2 resin (50 g). Thecolumn was washed with water (ca. 250 ml) and then eluted with methanol.Collection of the appropriate methanol fractions, and evaporation of thecombined fractions in vacuum gave 111 mg of

(±)-2-(3-diisopropylamino-1-phenylpropyl)-4-(1β-D-glucuronosyloxymethyl)-phenol,sodium salt, amorphous colourless solid, m.p.≅110-124° C. (dec.), tlc(4) 0.12. NMR (CD₃OD, major isomer): 19.43, 19.67, 33.26, 39.63, 42.27,48.23, 69.76, 73.55, 74.70, 75.95, 78.03, 107.64, 117.95, 125.51,127.36, 128.33, 133.83, 134.77, 144.49, 155.36, 176.76.

II. INCUBATIONS OF DIFFERENT COMPOUNDS OF THE INVENTION WITH HUMAN LIVERS 9-FRACTION a) Incubation of Unlabelled Substrates

A pooled human liver S 9-preparation was used to show the in-vitrometabolism of different compounds of the invention and to prove thegeneration of the active metabolite by enzymatic process.

The pooled human liver S 9-preparation was delivered by Gentest, Woburn,Mass., USA.

In a routine assay, 25 μL of pooled human liver S9 (20 mg protein/mL,H961, Gentest, Woburn, Mass., USA) was incubated for 2 hrs at 37° C.with 40 μM substrate in a 0.01 M potassium phosphate buffer in thepresence of NADPH (1 mM). The reaction was quenched by the addition ofconcentrated perchloric acid and precipitating protein was removed bycentrifugation. The supernatant was adjusted to pH 3 with concentratedpotassium phosphate solution, centrifuged, and injected into the HPLCfor analysis of the respective products.

The analysis of the non-deuterated compounds was performed by a routineHigh Pressure Liquid Chromatography (HPLC) method with UV-detection.

The incubation results expressed in (%) of theoretical turnover arepresented in FIG. 1.

They ranged from 96 to 63.2%. The formation of the active metabolite isdependent on the substituents both at the benzylic and phenolic side ofthe respective compounds.

Explanation:

The prodrugs introduced in the assay show the following chemicalstructure:

chemical structure X—/—YAcO—/—OAc means acetateHO—/—OBut means hydroxy and n-butyrateHO—/—OiBut means hydroxy and iso-butyrateiButO—/—OiBut means iso-butyrateButO—/—OBut means n-butyratePropO—/—OProp means proprionateHO—/—OProp means hydroxy and proprionateHO—/—OAc means hydroxy and acetateBzO—/—OBz means benzoate and benzoateAcO—/—OiBut means acetate and isobutyrateAcO—/—OBz means acetate and benzoate

b) Incubation of Labelled Substrates

The metabolic degradation of the unlabelled hydroxy metabolite (i.e.Intermediate B) and the deuteriated hydroxy-metabolite (Intermediated₂B) were compared in vitro. Used were the respective enantiomers andthe racemates.

The hydroxy metabolite and the deuteriated hydroxy-metabolite expressedsignificant differences in the rate to produce the correspondingcarboxylic acid.

The measurement was performed with an incubation time of 3 hrs at 37.0°C. in a concentration of 40 μM. The formation of the carboxylic acidfrom the deuteriated hydroxy-metabolite showed a significantly decreasedvelocity of 10%.

These in-vitro experiments indicate a reduced metabolic turnover of thedeuteriated compound in vitro, which may result in higher plasma levels.

c) Receptor Binding Study

WO 94/11337 discloses that the active metabolite has high affinity tomuscarinic receptors in the guinea-pig bladder. Different compounds ofthe present invention were tested in a well established standardizedassay, measuring the binding of [³H]-methylscopolamine to recombinanthuman M3 receptors. BSR-M3H cells transfected with a plasmid encodingthe human muscarinic M3 receptor were used to prepare membranes inmodified Tris-HCl pH 7.4 buffer using standard techniques. An aliquot ofthe membrane preparation was incubated with [³H]-methylscopolamine inthe presence or absence of different concentrations of several compoundsof the invention for 60 minutes at 25° C. Nonspecific binding wasestimated in the presence of 1 μM atropine. Membranes were filtered andwashed three times and the filters were counted to determine the amountof [³H]-methylscopolamine specifically bound. The following table showsthe IC₅₀ values of several compounds of the invention in the M3 receptorbinding assay.

Interaction with Human M3 Receptors In Vitro.

Prodrug IC₅₀ [nM] (+)HO—/—OH 8.7 (−)HO—/—OH 1300 (+)HO—/—OiBut 159(+)HO—/—OBz 172 BzO—/—OBz 2400 AcO—/—OiBut 3600 AcO—/—OBz 5400

These data clearly showed that derivatization at the phenolic hydroxylmoiety results in an about 20 times less potent binding. If bothfunctionalities are derivatized, the binding is even more dramaticallyreduced. Furthermore, it is demonstrated that the enantiomers of theactive metabolite exhibit a marked difference in the bindingcharacteristics to human M3 receptors.

The compounds were tested for their anticholinergic activity in astandard tissue assay, the guinea-pig ileum. A segment of ileum wasobtained from Duncan Hartley guinea-pigs which were sacrified bycervical dislocation. The tissue was placed under 1 g tension in a 10 mlbath containing Krebs' solution (pH 7.4, 32° C.) and theconcentration-dependent ability of different compounds to reduce themethacholine-induced (0.6 μM) contractile response was recorded. TheIC₅₀ values for the different substances were calculated and examplesare presented in the following table.

Anticholinergic activity in guinea-pig ileum in vitro

Prodrug IC₅₀ [nM] (+)HO—/—OH 20 (−)HO—/—OH 680 (+)HO—/—OiBut 57(+)HO—/—OBz 180 (+)BzO—/—OBz 220 (+)AcO—/—OiBut 240

These data confirm the results obtained in the receptor binding assaysand demonstrate that the anticholinergic activity of the compoundsdecreases with increased derivatization.

d) Biological Membranes

Different compounds of the invention were tested for their ability topenetrate the human skin (200 μm thick) in the “Flow through cell” at32° C. according to Tiemessen et al. (Acta Pharm. Technol. 1998;34:99-101). Phosphate buffer (pH 6.2) was used as the acceptor medium.Samples were drawn at different time points and analysed by RP-HPLC withUV detection (220 nm). Permeation profiles were plotted and mean fluxrates of different substances were calculated by linear regressionanalysis. The data obtained for different compounds of the invention aresummarized in the following table.

Penetration Through Human Skin

Flux rate Prodrug [μg/cm²/24 hrs] HO—/—OH 3 HO—/—OiBut 150 iButO—/—OiBut60 PropO—/—OProp 70

Disubstitution of the hydroxy group of HO—/—OH leads to a ≧20-foldincrease in skin permeation in relation to the parent HO—/—OH.Suprisingly monosubstitution of the penolic hydroxy group resulted ineven higher 50-fold penetration rate through human skin.

Taken together, these biological data clearly demonstrate that thecompounds of the invention have a reduced affinity to bind to humanmuscarinic M3 receptors. They exhibit an increased penetration throughbiological membranes, e.g. the human skin, and they are rapidlytransformed to the active metabolite, once they have entered thesystemic circulation as shown by the in vitro metabolism by the humanliver S9 preparation.

Thus, the antimuscarinic prodrugs according to this invention showed aprofile that defines excellent prodrugs.

1. 3,3-Diphenylpropylamines of the general formula

wherein: R¹ is hydrogen and R² is C₁-C₆ alkylcarbonyl; or R¹ is C₁-C₆alkylcarbonyl and R² is hydrogen; their salts with physiologicallyacceptable acids, their free bases and, when the3,3-Diphenylpropylamines are in the form of optical isomers, the racemicmixture and the individual enantiomers.
 2. The 3,3-Diphenylpropylamineof claim 1 wherein R¹ is hydrogen and R² is C₁-C₆ alkylcarbonyl.
 3. The3,3-Diphenylpropylamine of claim 1 wherein R¹ is C₁-C₆ alkylcarbonyl andR² is hydrogen.
 4. A method of treating urinary incontinence in apatient in need thereof, the method comprising administering to thepatient an effective amount of a 3,3-Diphenylpropylamine of the generalformula

wherein: R¹ is hydrogen and R² is C₁-C₆ alkylcarbonyl; or R¹ is C₁-C₆alkylcarbonyl and R² is hydrogen; or its salt with a physiologicallyacceptable acid, its free base or, when the 3,3-Diphenylpropylamine isin the form of optical isomers, the racemic mixture and the individualenantiomers.
 5. The method of claim 4 wherein R¹ is hydrogen and R² isC₁-C₆ alkylcarbonyl.
 6. The method of claim 4 wherein R¹ is C₁-C₆alkylcarbonyl and R² is hydrogen.
 7. The method according to any one ofclaims 4-6, wherein the 3,3-Diphenylpropylamine is administered to thepatient in the form of a pharmaceutical composition comprising apharmaceutically acceptable carrier.
 8. A pharmaceutical compositioncomprising an effective amount of a 3,3-Diphenylpropylamine according toany one of claims 1-3 and a pharmaceutically acceptable carrier.